Aims. Accurate skeletal age and final adult height prediction methods in paediatric orthopaedics are crucial for determining optimal timing of growth-guiding interventions and minimizing complications in treatments of various conditions. This study aimed to evaluate the accuracy of final adult height predictions using the central peak height (CPH) method with long leg X-rays and four different multiplier tables. Methods. This study included 31 patients who underwent temporary hemiepiphysiodesis for varus or valgus deformity of the leg between 2014 and 2020. The skeletal age at surgical intervention was evaluated using the CPH method with long leg radiographs. The true final adult height (FH. TRUE. ) was determined when the growth plates were closed. The final height prediction accuracy of four different multiplier tables (1. Bayley and Pinneau; 2. Paley et al; 3. Sanders – Greulich and Pyle (SGP); and 4. Sanders – peak height velocity (PHV)) was then compared using either skeletal age or chronological age. Results. All final adult height predictions overestimated the FH. TRUE. , with the SGP multiplier table having the lowest overestimation and lowest absolute deviation when using both chronological age and skeletal age. There were no significant differences in final height prediction accuracy between using skeletal age and chronological age with PHV (p = 0.652) or SGP multiplier tables (p = 0.969). Adult height predictions with chronological age and SGP (r = 0.769; p ≤ 0.001), as well as chronological age and PHV (r = 0.822; p ≤ 0.001), showed higher correlations with FH. TRUE. than predictions with skeletal age and SGP (r = 0.657; p ≤ 0.001) or skeletal age and PHV (r = 0.707; p ≤ 0.001). Conclusion. There was no significant improvement in adult height prediction accuracy when using the CPH method compared to chronological age alone. The study concludes that there is no advantage in routinely using the CPH method for skeletal age determination over the simple use of chronological age. The findings highlight the need for more accurate methods to predict final adult height in contemporary patient populations. Cite this article: Bone Jt Open 2023;4(10):750–757

Aims. The development of lumbar lordosis has been traditionally examined using angular measurements of the spine to reflect its shape. While studies agree regarding the increase in the angles during growth, the growth rate is understudied, and sexual dimorphism is debated. In this study, we used a novel method to estimate the shape of the lumbar curve (LC) using the landmark-based geometric morphometric method to explore changes in LC during growth, examine the effect of size and sex on LC shape, and examine the associations between angular measurements and shape. Methods. The study population included 258 children aged between 0 and 20 years (divided into five age groups) who underwent a CT scan between the years 2009 and 2019. The landmark-based geometric morphometric method was used to capture the LC shape in a sagittal view. Additionally, the lordosis was measured via Cobb and sacral slope angles. Multivariate and univariate statistical analyses were carried out to examine differences in shape between males and females and between the age groups. Results. The overall shape of the LC overlapped between males and females in most age groups, except for the nine- to 12-year age group. However, size did not affect LC shape. LC shape changed significantly during growth from straight to curved, reaching its mature shape earlier in females. This corresponded with the results obtained by the lordosis and sacral slope angles. A significant positive correlation was found between the LC shape and angles, although the angles demonstrated poor distinction between age groups, as opposed to the LC shape. Conclusion. New insights into LC shape development were achieved using the geometric morphometric method. The LC shape was sex-independent in most age groups. However, the LC reached its mature shape earlier in females than males. The method and data of this study are beneficial for future studies examining aetiological factors for spinal pathologies and maldevelopment. Cite this article: Bone Joint Res 2025;14(1):58–68

Aims. The prevalence of scoliosis is not known in patients with idiopathic short stature, and the impact of treatment with recombinant human growth hormone on those with scoliosis remains controversial. We investigated the prevalence of scoliosis radiologically in children with idiopathic short stature, and the impact of treatment with growth hormone in a cross-sectional and retrospective cohort study. Methods. A total of 2,053 children with idiopathic short stature and 4,106 age- and sex-matched (1:2) children without short stature with available whole-spine radiographs were enrolled in the cross-sectional study. Among them, 1,056 with idiopathic short stature and 790 controls who had radiographs more than twice were recruited to assess the development and progression of scoliosis, and the need for bracing and surgery. Results. In the cross-sectional study, there was an unexpectedly higher prevalence of scoliosis (33.1% (681/2,053) vs 8.52% (350/4,106)) in children with idiopathic short stature compared with controls (odds ratio 3.722; p < 0.001), although most cases were mild. In the longitudinal study, children with idiopathic short stature had a higher risk of the development and progression of scoliosis than the controls. Among children with idiopathic short stature without scoliosis at baseline, treatment with growth hormone significantly increased the risk of developing scoliosis (p = 0.015) and the need for bracing (p < 0.001). Among those with idiopathic short stature and scoliosis at baseline, treatment with growth hormone did not increase the risk of progression of the scoliosis, the need for bracing, or surgery. Conclusion. The impact of treatment with growth hormone on scoliosis in children with idiopathic short stature was considered controllable. However, physicians should pay close attention to the assessment of spinal curves in these children. Cite this article: Bone Joint J 2023;105-B(4):439–448

Aims. Osteoarthritis (OA) is the most prevalent systemic musculoskeletal disorder, characterized by articular cartilage degeneration and subchondral bone (SCB) sclerosis. Here, we sought to examine the contribution of accelerated growth to OA development using a murine model of excessive longitudinal growth. Suppressor of cytokine signalling 2 (SOCS2) is a negative regulator of growth hormone (GH) signalling, thus mice deficient in SOCS2 (Socs2. -/-. ) display accelerated bone growth. Methods. We examined vulnerability of Socs2. -/-. mice to OA following surgical induction of disease (destabilization of the medial meniscus (DMM)), and with ageing, by histology and micro-CT. Results. We observed a significant increase in mean number (wild-type (WT) DMM: 532 (SD 56); WT sham: 495 (SD 45); knockout (KO) DMM: 169 (SD 49); KO sham: 187 (SD 56); p < 0.001) and density (WT DMM: 2.2 (SD 0.9); WT sham: 1.2 (SD 0.5); KO DMM: 13.0 (SD 0.5); KO sham: 14.4 (SD 0.7)) of growth plate bridges in Socs2. -/-. in comparison with WT. Histological examination of WT and Socs2. -/-. knees revealed articular cartilage damage with DMM in comparison to sham. Articular cartilage lesion severity scores (mean and maximum) were similar in WT and Socs2. -/-. mice with either DMM, or with ageing. Micro-CT analysis revealed significant decreases in SCB thickness, epiphyseal trabecular number, and thickness in the medial compartment of Socs2. -/-. , in comparison with WT (p < 0.001). DMM had no effect on the SCB thickness in comparison with sham in either genotype. Conclusion. Together, these data suggest that enhanced GH signalling through SOCS2 deletion accelerates growth plate fusion, however this has no effect on OA vulnerability in this model. Cite this article: Bone Joint Res 2022;11(3):162–170

Aims. Temporary hemiepiphysiodesis (HED) is applied to children and adolescents to correct angular deformities (ADs) in long bones through guided growth. Traditional Blount staples or two-hole plates are mainly used for this indication. Despite precise surgical techniques and attentive postoperative follow-up, implant-associated complications are frequently described. To address these pitfalls, a flexible staple was developed to combine the advantages of the established implants. This study provides the first results of guided growth using the new implant and compares these with the established two-hole plates and Blount staples. Methods. Between January 2013 and December 2016, 138 patients (22 children, 116 adolescents) with genu valgum or genu varum were treated with 285 flexible staples. The minimum follow-up was 24 months. These results were compared with 98 patients treated with 205 two-hole plates and 92 patients treated with 535 Blount staples. In long-standing anteroposterior radiographs, mechanical axis deviations (MADs) were measured before and during treatment to analyze treatment efficiency. The evaluation of the new flexible staple was performed according to the idea, development, evaluation, assessment, long-term (IDEAL) study framework (Stage 2a). Results. Overall, 79% (109/138) of patients treated with flexible staples achieved sufficient deformity correction. The median treatment duration was 16 months (interquartile range (IQR) 8 to 21). The flexible staples achieved a median MAD correction of 1.2 mm/month/HED site (IQR 0.6 to 2.0) in valgus deformities and 0.6 mm/month/HED site (IQR 0.2 to 1.5) in varus deformities. Wound infections occurred in 1%, haematomas and joint effusions in 4%, and implant-associated complications in 1% of patients treated with flexible staples. Valgus AD were corrected faster using flexible staples than two-hole plates and Blount staples. Furthermore, the median MAD after treatment was lower in varus and valgus AD, fewer implant-associated complications were detected, and reduced implantation times were recorded using flexible staples. Conclusion. The flexible staple seems to be a viable option for guided growth, showing comparable or possibly better results regarding correction speed and reducing implant-associated complications. Further comparative studies are required to substantiate these findings. Cite this article: Bone Joint J 2023;105-B(3):331–340

Aims. The aim of this study was to compare outcomes of guided growth and varus osteotomy in treating Kalamchi type II avascular necrosis (AVN) after open reduction and Pemberton acetabuloplasty for developmental dysplasia of the hip (DDH). Methods. This retrospective study reviewed patients undergoing guided growth or varus osteotomy for Kalamchi type II AVN between September 2009 and January 2019. All children who had undergone open reduction and Pemberton acetabuloplasty for DDH with a minimum two-year follow-up were enrolled in the study. Demographic and radiological data, which included the head-shaft angle (HSA), neck-shaft angle (NSA), articulotrochanteric distance (ATD), Sharp angle (SA), and lateral centre-edge angle (LCEA) at baseline, two years, and at the extended follow-up, were compared. Revision rates were evaluated. Clinical outcomes using the Harris Hip Score were assessed two years postoperatively. Results. A total of 24 patients underwent guided growth and 19 underwent varus osteotomy, over a mean period of 3.3 years (95% confidence interval (CI) 2.8 to 3.8) and 5.2 years (95% CI 4.5 to 6.0), respectively. There were no differences in demographic and preoperative radiological data, except for a younger age at time of acetabuloplasty and larger ATD for the osteotomy group. The HSA did not differ at two years and the extended follow-up because of postoperative rebound in the osteotomy group. The NSA of the osteotomy group remained smaller postoperatively. There were no significant differences in the follow-up ATD, SA, and LCEA, except for a smaller two-year ATD of the osteotomy group. Seven patients (29.2%) in the guided growth group underwent revision surgery and none in the osteotomy group. The Harris Hip Score was similar between groups. Conclusion. Guided growth and varus osteotomy had comparable results in improving caput valgum deformity, given the rebound of lateral tilting of the physis after osteotomy correction. There were no differences in clinical outcomes at two years postoperatively. Cite this article: Bone Joint J 2022;104-B(7):902–908

Aims. Here we introduce a wide and complex study comparing effects of growth factors used alone and in combinations on human mesenchymal stem cell (hMSC) proliferation and osteogenic differentiation. Certain ways of cell behaviour can be triggered by specific peptides – growth factors, influencing cell fate through surface cellular receptors. Methods. In our study transforming growth factor β (TGF-β), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF) were used in order to induce osteogenesis and proliferation of hMSCs from bone marrow. These cells are naturally able to differentiate into various mesodermal cell lines. Effect of each factor itself is pretty well known. We designed experimental groups where two and more growth factors were combined. We supposed cumulative effect would appear when more growth factors with the same effect were combined. The cellular metabolism was evaluated using MTS assay and double-stranded DNA (dsDNA) amount using PicoGreen assay. Alkaline phosphatase (ALP) activity, as early osteogenesis marker, was observed. Phase contrast microscopy was used for cell morphology evaluation. Results. TGF-β and bFGF were shown to significantly enhance cell proliferation. VEGF and IGF-1 supported ALP activity. Light microscopy showed initial extracellular matrix mineralization after VEGF/IGF-1 supply. Conclusion. A combination of more than two growth factors did not support the cellular metabolism level and ALP activity even though the growth factor itself had a positive effect. This is probably caused by interplay of various messengers shared by more growth factor signalling cascades. Cite this article: Bone Joint Res 2020;9(7):412–420

Aims. Guided growth has been used to treat coxa valga for cerebral palsy (CP) children. However, there has been no study on the optimal position of screw application. In this paper we have investigated the influence of screw position on the outcomes of guided growth. Methods. We retrospectively analyzed 61 hips in 32 CP children who underwent proximal femoral hemi epiphysiodesis between July 2012 and September 2017. The hips were divided into two groups according to the transphyseal position of the screw in the coronal plane: across medial quarter (Group 1) or middle quarter (Group 2) of the medial half of the physis. We compared pre- and postoperative radiographs in head-shaft angle (HSA), Reimer’s migration percentage (MP), acetabular index (AI), and femoral anteversion angle (FAVA), as well as incidences of the physis growing-off the screw within two years. Linear and Cox regression analysis were conducted to identify factors related to HSA correction and risk of the physis growing-off the screw. Results. A total of 37 hips in Group 1 and 24 hips in Group 2 were compared. Group 1 showed a more substantial decrease in the HSA (p = 0.003) and the MP (p = 0.032). Both groups had significant and similar improvements in the AI (p = 0.809) and the FAVA (p = 0.304). Group 1 presented a higher incidence of the physis growing-off the screw (p = 0.038). Results of the regression analysis indicated that the eccentricity of screw position correlated with HSA correction and increases the risk of the physis growing-off the screw. Conclusion. Guided growth is effective in improving coxa valga and excessive femoral anteversion in CP children. For younger children, despite compromised efficacy of varus correction, we recommend a more centered screw position, at least across the middle quarter of the medial physis, to avoid early revision. Cite this article: Bone Joint J 2020;102-B(9):1242–1247

We studied 29 girls and one boy with adolescent idiopathic scoliosis who were at Risser grade 0 at the time of posterior spinal fusion and were followed until maturity (mean 7.8 years). We used serial radiographs to measure the ratio of disc to vertebral height in the fused segments and to detect differential anterior spinal growth and assess its effect on scoliosis, vertebral rotation, kyphosis, and rib-vertebral-angle difference (RVAD). From one year after surgery to the latest review, the percentage anterior disc height decreased by nearly one-half and the percentage posterior disc height by nearly one-third in the fused segments (p < 0.001). There was a 4 degree increase in mean Cobb angle (p < 0.001), 11 patients (37%) having an increase of between 6 degrees and 10 degrees. There was a significant increase in mean apical rotation by 2 degrees (p = 0.003), and four patients (13%) had an increase of between 6 degrees and 16 degrees. There was little change in kyphosis. There was an increase in mean RVAD by 4 degrees (p = 0.003), seven patients (23%) showing a reduction by 1 degree to 7 degrees, and 11 (37%) increases of between 6 degrees and 16 degrees. Spinal growth occurs after posterior fusion in adolescents who are skeletally immature, as a result of continued anterior vertebral growth. There is some progression of scoliosis, vertebral rotation, and RVAD, but little change in kyphosis. The increase in deformity is not enough to warrant the use of combined anterior and posterior fusion. The findings are relevant to the management of progressive curves, the timing and extent of surgery, and the prognosis for progression of deformity in this group of patients

Puppies in the second half of their growing period have been observed for one and a half to four and a half months after creation of a superficial femoral arteriovenous fistula on the right side. From measurements of the whole bone and from microradiographic and tetracycline-fluorophore studies of the diaphysial bone, it is believed that the following statistically significant phenomena may be attributed to the influence of the arteriovenous fistula. 1. All bones distal to the fistula are influenced in their growth. The tibia and metatarsals become heavier and larger, but retain normal shape. Although stimulation of longitudinal growth is small, it is significant for the tibiae and nearly significant for the femora in these short-term experiments. 2. The histological structure of the bones remains normal but quantitative changes are induced. The compact bone is more porous because of an increased number of osteones. Haversian turnover itself is affected in that the individual formation time of osteones tends to become longer, especially in the metatarsals. 3. Periosteal new bone formation is immediately stimulated, producing a flare of new bone. This accounts for the increase in diaphysial weight in the tibia but not in the metatarsals, where the same effect results from decreased resorption of old bone. 4. Endosteal new bone formation is depressed, especially in the metatarsals, resulting in an enlarged medullary cavity

Aims. We report the use of the distal radius and ulna (DRU) classification for the prediction of peak growth (PG) and growth cessation (GC) in 777 patients with idiopathic scoliosis. We compare this classification with other commonly used parameters of maturity. Patients and Methods. The following data were extracted from the patients’ records and radiographs: chronological age, body height (BH), arm span (AS), date of menarche, Risser sign, DRU grade and status of the phalangeal and metacarpal physes. The mean rates of growth were recorded according to each parameter of maturity. PG was defined as the summit of the curve and GC as the plateau in deceleration of growth. The rates of growth at PG and GC were used for analysis using receiver operating characteristic (ROC) curves to determine the strength and cutoff values of the parameters of growth. Results. The most specific grades for PG using the DRU classification were radial grade 6 and ulnar grade 5, and for GC were radial grade 9 and ulnar grade 7. The DRU classification spanned both PG and GC, enabling better prediction of these clinically relevant stages than other methods. The rate of PG (≥ 0.7 cm/month) and GC (≤ 0.15 cm/month) was the same for girls and boys, in BH and AS measurements. Conclusion. This is the first study to note that the DRU classification can predict both PG and GC, providing evidence that it may aid the management of patients with idiopathic scoliosis. Cite this article: Bone Joint J 2016;98-B:1689–96

Guiding growth by harnessing the ability of growing bone to undergo plastic deformation is one of the oldest orthopaedic principles. Correction of deformity remains a major part of the workload for paediatric orthopaedic surgeons and recently, along with developments in limb reconstruction and computer-directed frame correction, there has been renewed interest in surgical methods of physeal manipulation or ‘guided growth’. Manipulating natural bone growth to correct a deformity is appealing, as it allows gradual correction by non- or minimally invasive methods. This paper reviews the techniques employed for guided growth in current orthopaedic practice, including the basic science and recent advances underlying mechanical physeal manipulation of both healthy and pathological physes

Rebound growth after hemiepiphysiodesis may be a normal event, but little is known about its causes, incidence or factors related to its intensity. The aim of this study was to evaluate rebound growth under controlled experimental conditions. A total of 22 six-week-old rabbits underwent a medial proximal tibial hemiepiphysiodesis using a two-hole plate and screws. Temporal growth plate arrest was maintained for three weeks, and animals were killed at intervals ranging between three days and three weeks after removal of the device. The radiological angulation of the proximal tibia was studied at weekly intervals during and after hemiepiphysiodesis. A histological study of the retrieved proximal physis of the tibia was performed. The mean angulation achieved at three weeks was 34.7° (standard deviation (. sd). 3.4), and this remained unchanged for the study period of up to two weeks. By three weeks after removal of the implant the mean angulation had dropped to 28.2° (. sd. 1.8) (p < 0.001). Histologically, widening of the medial side was noted during the first two weeks. By three weeks this widening had substantially disappeared and the normal columnar structure was virtually re-established. In our rabbit model, rebound was an event of variable incidence and intensity and, when present, did not appear immediately after restoration of growth, but took some time to appear. Cite this article: Bone Joint J 2015;97-B:862–8

There is evidence to suggest that fractures heal more rapidly in patients with a head injury as a result of systemic factors released from the site of this injury. We have measured the circulating level of insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) in serum because of their known involvement in the stimulation of the activity of osteoblasts and the healing of fractures. The serum level of IGF-1 was significantly lower in patients with both head injury and fracture and fracture only compared with that in healthy volunteers (p < 0.01 and p < 0.02, respectively). The level of IGFBP-3 was also significantly lower in patients with both head injury and fracture (p < 0.01). Our findings showed, however, that the level of IGF-1 and IGFBP-3 varied from week to week in both the patients and healthy control subjects. These results indicate that the levels of circulating IGF-1 and IGFBP-3 are unlikely to be responsible for the altered healing of fractures seen in conjunction with head injury

Objectives. The injured anterior cruciate ligament (ACL) is thought to exhibit an impaired healing response, and attempts at surgical repair have not been successful. Connective tissue growth factor (CTGF) is reported to be associated with wound healing, probably through transforming growth factor beta 1 (TGF-β1). Methods. A rabbit ACL injury model was used to study the effect of CTGF on ligament recovery. Quantitative real-time PCR (qRT-PCR) was performed for detection of changes in RNA levels of TGF-β1, type 1 collagen (COL1), type 2 collagen (COL2), SRY-related high mobility group-box gene9 (SOX9), tissue inhibitor of metalloproteinase-1 (TIMP-1) and matrix metallopeptidase 13 (MMP-13). Expression of related proteins was detected by Western blotting. Results. The current study showed that CTGF could promote the recovery of an injured anterior cruciate ligament. It can upregulate mRNA and expression of TGF-β1, COL1, COL2, SOX9, and tissue inhibitor of TIMP-1, and downregulate mRNA and expression of MMP-13, suggesting that the curative effect of CTGF on injured rabbit ligaments is through regulation of these cellular factors. Conclusions. This finding revealed the healing role of CTGF in injured tissues and provides new possibilities of treating injured tissues and wound healing by using CTGF. Cite this article: X. Sun, W. Liu, G. Cheng, X. Qu, H. Bi, Z. Cao, Q. Yu. The influence of connective tissue growth factor on rabbit ligament injury repair. Bone Joint Res 2017;6:399–404. DOI: 10.1302/2046-3758.67.BJR.2016-0255.R1

The mammalian growth plate is a complex structure which is essential for the elongation of long bones. However, an understanding of how the growth plate functions at the cellular level is lacking. This review, summarises the factors involved in growth-plate regulation, its failure and the consequence of injury. We also describe some of the cellular mechanisms which underpin the increase in volume of the growth-plate chondrocyte which is the major determinant of the rate and extent of bone lengthening. We show how living in situ chondrocytes can be imaged using 2-photon laser scanning microscopy to provide a quantitative analysis of their volume. This approach should give better understanding of the cellular control of bone growth in both healthy and failed growth plates

Objectives. The aim of this experimental study on New Zealand’s white rabbits was to investigate the transplantation of autogenous growth plate cells in order to treat the injured growth plate. They were assessed in terms of measurements of radiological tibial varus and histological characteristics. . Methods. An experimental model of plate growth medial partial resection of the tibia in 14 New Zealand white rabbits was created. During this surgical procedure the plate growth cells were collected and cultured. While the second surgery was being performed, the autologous cultured growth plate cells were grafted at the right tibia, whereas the left tibia was used as a control group. . Results. Histological examinations showed that the grafted right tibia presented the regular shape of the plate growth with hypertrophic maturation, chondrocyte columniation and endochondral calcification. Radiological study shows that the mean tibial deformity at the left angle was 20.29° (6.25 to 33) and 7.21° (5 to 10) in the right angle. . Conclusion. This study has demonstrated that grafting of autogenous cultured growth plate cells into a defect of the medial aspect of the proximal tibial physis can prevent bone bridge formation, growth arrest and the development of varus deformity. Cite this article: Bone Joint Res 2014;3:310–16

Aims. The primary aim of this study was to evaluate the performance and safety of magnetically controlled growth rods in the treatment of early onset scoliosis. Secondary aims were to evaluate the clinical outcome, the rate of further surgery, the rate of complications, and the durability of correction. Patients and Methods. We undertook an observational prospective cohort study of children with early onset scoliosis, who were recruited over a one-year period and followed up for a minimum of two years. Magnetically controlled rods were introduced in a standardized manner with distractions performed three-monthly thereafter. Adverse events which were both related and unrelated to the device were recorded. Ten children, for whom relevant key data points (such as demographic information, growth parameters, Cobb angles, and functional outcomes) were available, were recruited and followed up over the period of the study. There were five boys and five girls. Their mean age was 6.2 years (2.5 to 10). Results. The mean coronal Cobb angle improved from 57.6° (40° to 81°) preoperatively, 32.8° (28° to 46°) postoperatively, and 41° (19° to 57°) at two years. Five children had an adverse event, with four requiring return to theatre, but none were related to the device. There were no neurological complications or infections. No devices failed. One child developed a proximal junctional kyphosis. The mean gain in spinal column height from T1 to S1 was 45.4 mm (24 to 81) over the period of the study. Conclusion. Magnetically controlled growth rods provide an alternative solution to traditional growing rods in the surgical management of children with early onset scoliosis, supporting growth of the spine while controlling curve progression. Their use has clear psychosocial and economic benefits, with the reduction of the need for repeat surgery as required with traditional growing rods. Cite this article: Bone Joint J 2018;100-B:507–15

In the majority of patients with slipped upper femoral epiphysis only one hip is involved at primary diagnosis. However, the contralateral hip often becomes involved over time. There are no reliable factors predicting a contralateral slip. Whether or not the contralateral hip should undergo prophylactic fixation is a matter of controversy. We present a number of essential points that have to be considered both when choosing to fix the contralateral hip prophylactically as well as when refraining from surgery and instead following the patients with repeat radiographs.

Objectives. Effects of insulin-like growth factor 1 (IGF1), fibroblast growth factor 2 (FGF2) and bone morphogenetic protein 2 (BMP2) on the expression of genes involved in the proliferation and differentiation of osteoblasts in culture were analysed. The best sequence of growth factor addition that induces expansion of cells before their differentiation was sought. Methods. Primary human osteoblasts in in vitro culture were treated with IGF1, BMP2 or FGF2 (10 ng/ml) for 24 hours (IGF1) or 48 hours (BMP2 and FGF2). Experiments were performed during the exponential growth phase with approximately 1e7 cells per 75 cm. 2. flask. mRNA was reverse transcribed directly and analysed using RT-PCR Taqman assays. Expression levels of key genes involved in cell growth and differentiation (CDH11, TNFRSF11B, RUNX2, POSTN, ALP, WNT5A, LEF1, HSPA5, FOS, p21) were monitored using RT-PCR with gene-specific Taqman probes. . Results. Autocrine expression of BMP2 is stimulated by FGF2 and BMP2 itself. BMP2 and FGF2 act as proliferative factors as indicated by reduced expression of ALP and POSTN, whereas IGF1 exhibits a more subtle picture: the Wingless und Int-1 (Wnt) signalling pathway and the Smad pathway, but not p38 mitogen-activated protein (MAP) kinase signalling, were shown to be activated by IGF1, leading to proliferation and differentiation of the cells. . Conclusions. For future use of autologous bone cells in the management of bony defects, new treatment options take advantage of growth factors and differentiation factors. Thus, our results might help to guide the timely application of these factors for the expansion and subsequent differentiation of osteoblastic cells in culture. Cite this article: Bone Joint Res 2014;3:236–40

In vivo animal experimentation has been one of the cornerstones of biological and biomedical research, particularly in the field of clinical medicine and pharmaceuticals. The conventional in vivo model system is invariably associated with high production costs and strict ethical considerations. These limitations led to the evolution of an ex vivo model system which partially or completely surmounted some of the constraints faced in an in vivo model system. The ex vivo rodent bone culture system has been used to elucidate the understanding of skeletal physiology and pathophysiology for more than 90 years. This review attempts to provide a brief summary of the historical evolution of the rodent bone culture system with emphasis on the strengths and limitations of the model. It encompasses the frequency of use of rats and mice for ex vivo bone studies, nutritional requirements in ex vivo bone growth and emerging developments and technologies. This compilation of information could assist researchers in the field of regenerative medicine and bone tissue engineering towards a better understanding of skeletal growth and development for application in general clinical medicine. Cite this article: A. A. Abubakar, M. M. Noordin, T. I. Azmi, U. Kaka, M. Y. Loqman. The use of rats and mice as animal models in ex vivo bone growth and development studies. Bone Joint Res 2016;5:610–618. DOI: 10.1302/2046-3758.512.BJR-2016-0102.R2

This paper describes a study in the human femur of the relationship between cell division in growth cartilage and overall bone growth. Growth rates for the distal femur from birth to eighteen years were determined from serial radiographs available from the Harpenden Growth Study; An average of 1-4 cm/year was found for the ages of five to eight years. The development of the growth plate is illustrated in a series of photomicrographs of femur sections. These sections were also used for quantitative histology; The length of the proliferation zone was estimated from cell counts to be twenty-four cells per column. On the basis of this value and the measured growth rate, an approximate mean cycle time of twenty days was found for the proliferating cells of the human growth plate. Since the corresponding cycle time is two days for rodent growth plates, which also have a different structure, it is unwise to extrapolate the findings in this tissue from mouse to man

We used a rabbit model to investigate the mechanism by which the angulation of fractures is corrected in children. We produced a transverse proximal tibial fracture in one leg of 12 eight-week-old New Zealand white rabbits and measured bone alignment and length and the patterns of bone growth and remodelling. The angle between the joint surfaces changed rapidly to correct the alignment of the limb as a result of asymmetrical growth of epiphyseal plates. In an adult with closed plates, the angle between the joint surfaces cannot therefore improve. The angle at the fracture itself showed slow improvement because of bone drift and the asymmetrical growth of the epiphyseal plates. Remodelling corrected the shape of the bone in the region of the fracture. Periosteal division on the convex side increased the growth of the epiphyseal plate on that side, thus slowing the correction. The effect was relatively small, providing an indication that factors other than the periosteum are important in inducing correction. External torsional deformities developed because of helical growth at the plate. This was probably caused by abnormal posture which induced a torque at the growth plate. Helical growth is the mechanism by which rotational deformities can occur and correct

Sex hormones play important roles in the regulation of the proliferation, maturation and death of chondrocytes in the epiphyseal growth plate. We have investigated the effects of male castration on the cell kinetics of chondrocytes as defined by the numbers of proliferating and dying cells. The growth plates of normal rabbits and animals castrated at eight weeks of age were obtained at 10, 15, 20 and 25 weeks of age. Our study suggested that castration led to an increase in apoptosis and a decrease in the proliferation of chondrocytes in the growth plate. In addition, the number of chondrocytes in the castrated rabbits was less than that of normal animals of the same age

1. Diametric growth and organisation of the epiphysial cartilage plate have been studied by microradiography of human bone and autoradiography of the epiphysial plate in growing rabbits, using sulphur. 35. These investigations were supplemented by a radiographic study of four patients with dyschondroplasia in whom the progress of the characteristic epiphysial defects were traced during several years' growth. 2. A perichondrial sheath of bone, at the junction of the epiphysial plate with the metaphysis, was demonstrated by microradiography of the distal end of the human femur. Its relationship to epiphysial growth is discussed. 3. Autoradiography, to determine the direction of the cellular proliferation between the epiphysial plate and the overlying perichondrium, demonstrated the appearance of new cartilage cells at the periphery of the plate over a period of six days. 4. The evidence presented strongly favours the postulate that the transverse diameter of the epiphysial cartilage plate increases by appositional growth from the overlying perichondrium and that the same source is responsible for lateral extension of the articular cartilage during growth

Objectives. The role of mechanical stress and transforming growth factor beta 1 (TGF-β1) is important in the initiation and progression of osteoarthritis (OA). However, the underlying molecular mechanisms are not clearly known. Methods. In this study, TGF-β1 from osteoclasts and knee joints were analyzed using a co-cultured cell model and an OA rat model, respectively. Five patients with a femoral neck fracture (four female and one male, mean 73.4 years (68 to 79)) were recruited between January 2015 and December 2015. Results showed that TGF-β1 was significantly upregulated in osteoclasts by cyclic loading in a time- and dose-dependent mode. The osteoclasts were subjected to cyclic loading before being co-cultured with chondrocytes for 24 hours. Results. A significant decrease in the survival rate of co-cultured chondrocytes was found. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL) assay demonstrated that mechanical stress-induced apoptosis occurred significantly in co-cultured chondrocytes but administration of the TGF-β1 receptor inhibitor, SB-505124, can significantly reverse these effects. Abdominal administration of SB-505124 can attenuate markedly articular cartilage degradation in OA rats. Conclusion. Mechanical stress-induced overexpression of TGF-β1 from osteoclasts is responsible for chondrocyte apoptosis and cartilage degeneration in OA. Administration of a TGF-β1 inhibitor can inhibit articular cartilage degradation. Cite this article: R-K. Zhang, G-W. Li, C. Zeng, C-X. Lin, L-S. Huang, G-X. Huang, C. Zhao, S-Y. Feng, H. Fang. Mechanical stress contributes to osteoarthritis development through the activation of transforming growth factor beta 1 (TGF-β1). Bone Joint Res 2018;7:587–594. DOI: 10.1302/2046-3758.711.BJR-2018-0057.R1

The parameters of cellular proliferation and growth in the growth plates of immature rats were measured after unilateral tibial osteotomy and used to calculate growth rates. Distal osteotomy of one tibia was followed by a bilateral increase in the calculated growth rate of the distal growth plates. However, the ipsilateral distal growth plate grew faster than the contralateral between 12 and 18 days after operation, which appeared to be related to increased cell proliferation and height. Proximal osteotomy led to an increase in growth rates proximally which was more marked on the contralateral side. The lesser response of the ipsilateral growth plate may have been due to local impairment of blood supply, or to greater local release of metabolites after bony damage. Distal tibial osteotomy gave similar results to circumferential release of the distal tibial periosteum. Proximal osteotomy, however, produced a relative impairment of growth on the operated side. This may be of importance in the correction of childhood deformities associated with inequality of leg length

Matrix metalloproteinases (MMPs), responsible for extracellular matrix remodelling and angiogenesis, might play a major role in the response of the growth plate to detrimental loads that lead to overuse injuries in young athletes. In order to test this hypothesis, human growth plate chondrocytes were subjected to mechanical forces equal to either physiological loads, near detrimental or detrimental loads for two hours. In addition, these cells were exposed to physiological loads for up to 24 hours. Changes in the expression of MMPs -2, -3 and -13 were investigated. We found that expression of MMPs in cultured human growth plate chondrocytes increases in a linear manner with increased duration and intensity of loading. We also showed for the first time that physiological loads have the same effect on growth plate chondrocytes over a long period of time as detrimental loads applied for a short period. These findings confirm the involvement of MMPs in overuse injuries in children. We suggest that training programmes for immature athletes should be reconsidered in order to avoid detrimental stresses and over-expression of MMPs in the growth plate, and especially to avoid physiological loads becoming detrimental. Cite this article: Bone Joint J 2013;95-B:568–73

The anatomy and development of the growing acetabulum are not clearly understood. We dissected and studied histologically two acetabula from the pelvis of a three-month-old infant. Relative rates of growth at the different growth plates were assessed by comparing the height of the proliferative layer with that of the hypertrophic layer. The three bones which form the acetabulum are surrounded by growth plates on all sides except medially. These face towards the centre of the triradiate cartilage, the limbs of the triradiate cartilage and the articular surface and each may be divided into four distinct areas according to the orientation of its cell columns which reflect the direction of growth. Growth was particularly rapid at the ischial growth plates directed towards the centre and the articular cartilage, and on both sides of the anterior limb of the triradiate cartilage. These findings may explain the mechanism by which the acetabulum changes orientation and inclination with growth

1. The widespread deformities commonly associated with diaphysial aclasis have been studied in seventy-six patients. Apart from the adaptations of growth due to pressure by neighbouring exostoses, all the deformities of the tubular bones can be explained in terms of the same underlying factor–diminished length of the bones affected by the disease. 2. When the condition first manifests itself the future pattern of bone growth is completely unpredictable except in so far as it is known that the more actively growing ends of the long bones are the more severely affected in each case. It has also been shown in this series that, in general, the bones with the smallest cross-sectional area at the epiphysial plates (such as the ulna and the fibula) are the most severely shortened of all. 3. The cause of this disturbance of growth is still unknown, but there is an undoubted relationship between the presence of exostoses or thickening of the metaphysial region and shortening of the bone involved. 4. The phenomena of migrating exostoses and disappearing exostoses are also described and are shown to be examples of the normal process of bone modelling applied in special circumstances. 5. Although the importance of the cartilage-capped exostoses is not underestimated, it is hoped that this study will stimulate further work on what is probably the basic defect in this disease–namely, the disturbance of bone growth

We report a case of spontaneous physeal growth arrest of the distal femur in a nine-year-old child with Ewing’s sarcoma of the proximal femur treated with chemotherapy and endoprosthetic replacement. Owing to the extent of disuse osteoporosis at the time of surgery, the entire intramedullary canal up to the distal femoral physis was filled with cement. Three years later, the femur remained at its pre-operative length of 19 cm. Pre-operative calculations of further growth failed to account for the growth arrest, and the initial expandable growing prosthesis inserted has been revised to a longer one in order to address the leg-length discrepancy. To our knowledge, this is the only reported case of distal femoral physeal growth arrest following cemented endoprosthetic replacement of the proximal femur

1. An experimental study of the effects of nerve and muscle lesions upon the growth of bone has been made. In each case animals were subjected to unilateral lesions in the hind limb, the other limb serving as a control. The growth of the tibia was measured by calculating the difference between the length of the bone on a radiograph at the beginning of the experiment and the length of the dried bone after necropsy. The weights of the dried bones were compared. 2. In the young rabbit simple exposure of the common peroneal nerve, or division of the sural nerve, produced no change in the growth rate of the tibia. Division of both peroneal nerves, producing paralysis of the muscles below the knee, led to lengthening of the affected tibia, and this lengthening persisted until maturity several months later. A similar lengthening was seen after division of the tendons around the ankle. In spite of this lengthening the tibia on the side of the operation was almost always lighter than its fellow. 3. In the puppy division of the anterior nerve roots supplying the hind limb produced a significant lengthening of the tibia of the affected limb three months after operation. No significant changes in limb length occurred after lumbar sympathectomy in the puppy. 4. The significance of these experimental nerve lesions has been considered together with recent observations upon the growth of bone in the presence of lower motor neurone lesions in the child. From this analysis it is suggested that the initial effect of paralysis is to produce lengthening of the affected bone. This lengthening is probably due to the hyperaemia of disuse. In the presence of persistent paralysis the growth of the limb is ultimately depressed. This depression is rarely seen in the experimental animal because the growing period is relatively short. The possible causes of this secondary depression of bone growth have been considered

Objectives. The aim of this study was to examine whether asymmetric loading influences macrophage elastase (MMP12) expression in different parts of a rat tail intervertebral disc and growth plate and if MMP12 expression is correlated with the severity of the deformity. Methods. A wedge deformity between the ninth and tenth tail vertebrae was produced with an Ilizarov-type mini external fixator in 45 female Wistar rats, matched for their age and weight. Three groups were created according to the degree of deformity (10°, 30° and 50°). A total of 30 discs and vertebrae were evaluated immunohistochemically for immunolocalisation of MMP12 expression, and 15 discs were analysed by western blot and zymography in order to detect pro- and active MMP12. Results. No MMP12 expression was detected in the nucleus pulposus. Expression of MMP12 in the annulus progressively increased from group I to groups II and III, mainly at the concave side. Many growth plate chondrocytes expressed MMP12 in the control group, less in group I and rare in groups II and III. Changes in cell phenotype and reduction of cell number were observed, together with disorganisation of matrix microstructure similar to disc degeneration. ProMMP12 was detected at the area of 54 kDa and active MMP12 at 22 kDa. Conclusions. Expression of MMP12 after application of asymmetric loading in a rat tail increased in the intervertebral disc but decreased in the growth plate and correlated with the degree of the deformity and the side of the wedged disc. Cite this article: Bone Joint Res 2014;3:273–9

We studied the cellular response to physeal distraction in the growth plates of skeletally immature rabbits. We used a new method of labelling and detection of proliferating cells with bromodeoxyuridine (BUdR) and an anti-BUdR antibody. The application of an external fixator but no distraction force produced no changes in the growth plates. After five days of distraction at a maximum force of 20 N, the growth plate became thicker, mainly because of an increase in the number of hypertrophic chondrocytes, but there was no evidence of increased cell proliferation. Recent fractures were seen at the junction of growth plate and metaphysis but the increase in bone length was insignificant. After ten days of distraction at the same maximum force, the chondrocyte columns had become disorganised and cell proliferation was significantly decreased. There was an increase in bone length due to distraction of the fracture gap. In this model, physeal distraction did not stimulate cell proliferation, but actually inhibited it. The apparent increase in growth-plate thickness produced by distraction is not due to increased cell production, but results from inhibition of endochondral ossification and the consequent accumulation of hypertrophic chondrocytes. Any growth after distraction depends on the ability of growth-plate chondrocytes to divide. The decrease in proliferative activity which we found after ten days of distraction suggests the need for caution in the use of such procedures in young children

Injury to muscles is very common. We have previously observed that basic fibroblast growth factor (b-FGF), insulin growth factor type 1 (IGF-1) and nerve growth factor (NGF) are potent stimulators of the proliferation and fusion of myoblasts in vitro. We therefore injected these growth factors into mice with lacerations of the gastrocnemius muscle. The muscle regeneration was evaluated at one week by histological staining and quantitative histology. Muscle healing was assessed histologically and the contractile properties were measured one month after injury. Our findings showed that b-FGF, IGF and to a less extent NGF enhanced muscle regeneration in vivo compared with control muscle. At one month, muscles treated with IGF-1 and b-FGF showed improved healing and significantly increased fast-twitch and tetanus strengths. Our results suggest that b-FGF and IGF-1 stimulated muscle healing and may have a considerable effect on the treatment of muscle injuries

We report our results in 24 children with malignant primary bone tumours of the distal femur treated with a Stanmore extendible endoprosthesis (SEER). This consists of a femoral component that can be lengthened, a constrained knee and an uncemented sliding tibial component which crosses the proximal tibial physeal plate perpendicularly. The average age of the patients at diagnosis was ten years and the mean follow-up was 4.7 years (2.5 to 7.9). The mean growth of the affected tibia was 76% (18 to 136) and of the fibula 83% (15 to 750) of the growth of the unaffected limb. Measurement of growth arrest lines showed that the mean growth of the proximal tibial physis on the affected side was 69% (43 to 100) of that of the normal side. The great variability in the growth of the physis cannot yet be explained

McFarland fractures of the medial malleolus in children, also classified as Salter–Harris Type III and IV fractures, are associated with a high incidence of premature growth plate arrest. In order to identify prognostic factors for the development of complications we reviewed 20 children with a McFarland fracture that was treated surgically, at a mean follow-up of 8.9 years (3.5 to 17.4). Seven children (35%) developed premature growth arrest with angular deformity. The mean American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale for all patients was 98.3 (87 to 100) and the mean modified Weber protocol was 1.15 (0 to 5). There was a significant correlation between initial displacement (p = 0.004) and operative delay (p = 0.007) with premature growth arrest. Both risk factors act independently and additively, such that all children with both risk factors developed premature arrest whereas children with no risk factor did not. We recommend that fractures of the medial malleolus in children should be treated by anatomical reduction and screw fixation within one day of injury. Cite this article: Bone Joint J 2013;95-B:419–23

Glenoid replacement is technically challenging. Removal of a cemented glenoid component often results in a large osseous defect which makes the immediate introduction of a revision prosthesis almost impossible. We describe a two-stage revision procedure using a reversed shoulder prosthesis. Freeze-dried allograft with platelet-derived growth factor was used to fill the glenoid defect. Radiological incorporation of the allograft was seen and its consistency allowed the placement of a screwed glenoid component. There were no signs of new mature bone formation on histological examination. The addition of platelet-derived growth factor to the allograft seems to contribute to an increase in incorporation and hardness, but does not promote the growth of new bone

1. Arrest of growth at one proximal tibial epiphysis of young rabbits was obtained by stapling. 2. Radiopaque markers allowed the subsequent growth of both proximal and distal epiphyses of the experimental and contralateral tibiae and of both lower femoral epiphyses to be followed radiographically. 3. The reduction in the normal deceleration of growth rate at the distal epiphysis found after epiphysiodesis of the proximal epiphysis was again observed. 4. This change in growth rate was not encountered in the distal femoral epiphysis lying adjacent to the stapled tibial epiphysis. 5. Removal of the staples after the change in growth rate had become established at the distal tibial epiphysis was followed by a return to an approximately normal growth rate by both proximal and distal epiphyses. 6. It is concluded that a direct relationship exists between the additional growth at the uninjured epiphysis and the deficiency in growth obtained at the stapled epiphysis, and that this change in growth rate is limited to the experimental tibia

1. Small indian ink marks were made at intervals along the length of tendons in the limbs of young rabbits, and the distance between the marks was measured during the operation. The rabbits were killed two to three months later, and the amount of longitudinal growth that had occurred was determined by re-measuring the distance between the marks. 2. The experiments showed that the whole of the tendon grows interstitially in length, but that maximal growth occurs near the muscle-tendon junction. 3. Histological examination of the tendons and control experiments involving adult tendons indicated that growth was not significantly interfered with by marking the tendons

1. Homografts of eighteen-day-old foetal femora in pure strains of mice showed no fundamental difference in behaviour from grafts of more mature bone and cartilage. 2. Growth of bone was limited to a short period after transplantation and was abolished by previous immunisation. Cartilage growth alone was responsible for the increase in size of these transplants and did not appear to be influenced by the presence of immunity. 3. There is no reason to suppose that bone from an immature source is likely to behave more favourably than more mature bone homografts in clinical use. 4. The limited growth of cartilage and the total failure of bone survival in the heterografts indicate an immune reaction ofa different order from that which develops against the homograft. 5. The different effect of the homograft immune reaction on cartilage and bone enabled certain conclusions to be drawn concerning the part played by these two tissues in determining the form of a bone. Cartilage growth and development is shown to be regulated in large part by intrinsic factors. Bone growth and form on the other hand is shown to be dependent largely upon extrinsic influences

1. Experimental epiphysiodesis was performed on either the upper or lower epiphysial cartilage of one tibia of young rabbits, the other tibia serving as a control. 2. Subsequent growth was observed at each epiphysis by radiography. 3. After both operations the normal deceleration of growth rate of the uninjured epiphysis on the experimental side was reduced and this epiphysis made a greater contribution than its control to the final length of the bone. 4. Serial sections of the injured epiphysis revealed that the arrest of growth was due to the formation of a narrow bony bridge between the epiphysial and metaphysial bone. 5. The additional growth of the uninjured epiphysis appeared to have a direct relationship to the deficiency of growth at the epiphysis that had been injured by operation. 6. The results may indicate the existence of a local system of growth control

The effects of gamma irradiation on the growth plate have been studied in nineteen rabbits with a 1,000 rads/skin dose. The rabbits were killed after one to ninety days. The growth plates were studied by microscopic examination, thymidine-H3 autoradiography, and fluorescence with radiographic measurement. Changes were already detected after twenty-four hours at the cell mitosis level, which showed the sensitiveness of the chondrocyte itself. The lesions were clearly seen with the optical microscope after seven days, and they were most advanced between the fourteenth and twenty-first day after irradiation. Regeneration of the cartilage began in the fourth week and the histological appearance became normal after seventy days. Fluorescence with tetracycline showed a temporary retardation of growth, with consequent shortening of the affected limb

This study evaluated the effect of limb lengthening on longitudinal growth in patients with achondroplasia. Growth of the lower extremity was assessed retrospectively by serial radiographs in 35 skeletally immature patients with achondroplasia who underwent bilateral limb lengthening (Group 1), and in 12 skeletally immature patients with achondroplasia who did not (Group 2). In Group 1, 23 patients underwent only tibial lengthening (Group 1a) and 12 patients underwent tibial and femoral lengthening sequentially (Group 1b). The mean lengthening in the tibia was 9.2 cm (59.5%) in Group 1a, and 9.0 cm (58.2%) in the tibia and 10.2 cm (54.3%) in the femur in Group 1b. The mean follow-up was 9.3 years (8.6 to 10.3). The final mean total length of lower extremity in Group 1a was 526.6 mm (501.3 to 552.9) at the time of skeletal maturity and 610.1 mm (577.6 to 638.6) in Group 1b, compared with 457.0 mm (411.7 to 502.3) in Group 2. However, the mean actual length, representing the length solely grown from the physis without the length of distraction, showed that there was a significant disturbance of growth after limb lengthening. In Group 1a, a mean decrease of 22.4 mm (21.3 to 23.1) (4.9%) was observed in the actual limb length when compared with Group 2, and a greater mean decrease of 38.9 mm (37.2 to 40.8) (8.5%) was observed in Group 1b when compared with Group 2 at skeletal maturity. In Group 1, the mean actual limb length was 16.5 mm (15.8 to 17.2) (3.6%) shorter in Group 1b when compared with Group 1a at the time of skeletal maturity. Premature physeal closure was seen mostly in the proximal tibia and the distal femur with relative preservation of proximal femur and distal tibia. We suggest that significant disturbance of growth can occur after extensive limb lengthening in patients with achondroplasia, and therefore, this should be included in pre-operative counselling of these patients and their parents

Frozen shoulder is a chronic fibrosing condition of the capsule of the joint. The predominant cells involved are fibroblasts and myofibroblasts which lay down a dense matrix of type-I and type-III collagen within the capsule. This subsequently contracts leading to the typical features of pain and stiffness. Cytokines and growth factors regulate the growth and function of the fibroblasts of connective tissue and remodelling of the matrix is controlled by the matrix metalloproteinases (MMPs) and their inhibitors. Our aim was to determine whether there was an abnormal expression or secretion of cytokines, growth factors and MMPs in tissue samples from 14 patients with frozen shoulder using the reverse transcription/polymerase chain reaction (RT/PCR) technique and to compare the findings with those in tissue from four normal control shoulders and from five patients with Dupuytren’s contracture. Tissue from frozen shoulders demonstrated the presence of mRNA for a large number of cytokines and growth factors although the frequency was only slightly higher than in the control tissue. The frequency for a positive signal for the proinflammatory cytokines Il-1β and TNF-α and TNF-β, was not as great as in the Dupuytren’s tissue. The presence of mRNA for fibrogenic growth factors was, however, more similar to that obtained in the control and Dupuytren’s tissue. This correlated with the histological findings which in most specimens showed a dense fibrous tissue response with few cells other than mature fibroblasts and with very little evidence of any active inflammatory cell process. Positive expressions of the mRNA for the MMPs were also increased, together with their natural inhibitor TIMP. The notable exception compared with control and Dupuytren’s tissue was the absence of MMP-14, which is known to be a membrane-type MMP required for the activation of MMP-2 (gelatinase A). Understanding the control mechanisms which play a part in the pathogenesis of frozen shoulder may lead to the development of new regimes of treatment for this common, protracted and painful chronic fibrosing condition

The aim of this study was to evaluate whether coating titanium discs with selenium in the form of sodium selenite decreased bacterial adhesion of Staphylococcus aureus and Staph. epidermidis and impeded osteoblastic cell growth. In order to evaluate bacterial adhesion, sterile titanium discs were coated with increasing concentrations of selenium and incubated with bacterial solutions of Staph. aureus (ATCC 29213) and Staph. epidermidis (DSM 3269) and stained with Safranin-O. The effect of selenium on osteoblastic cell growth was also observed. The adherence of MG-63 cells on the coated discs was detected by staining with Safranin-O. The proportion of covered area was calculated with imaging software. The tested Staph. aureus strain showed a significantly reduced attachment on titanium discs with 0.5% (p = 0.011) and 0.2% (p = 0.02) selenium coating. Our test strain from Staph. epidermidis showed a highly significant reduction in bacterial adherence on discs coated with 0.5% (p = 0.0099) and 0.2% (p = 0.002) selenium solution. There was no inhibitory effect of the selenium coating on the osteoblastic cell growth. Selenium coating is a promising method to reduce bacterial attachment on prosthetic material. Cite this article: Bone Joint J 2013;95-B:678–82

1. A brief description is given of normal epiphysial growth of the human femur. 2. Some ways in which abnormality of the growth plates may affect the shape and length of the human femur are described. 3. The influence of the blood supply on growth is discussed with particular reference to the etiology and treatment of congenital coxa vara

In this study of fractures of the shaft of the tibia and femur in children, the growth rate of these long bones after injury was assessed by serial radiographical measurements of bone length, accurate to the nearest millimetre. Within three months of injury the rate of growth was at its maximum and was 38 per cent in excess of normal. The rate then decreased but remained significantly raised for two years and returned to normal in the tibia approximately 40 months after injury and in the femur between 50 and 60 months. The uninjured tibia in the same limb as a fractured femur also underwent an acceleration of growth, but to a lesser degree. An uninjured femur was not so affected by an injured tibia. The growth rate in these limbs was unaffected by the age or sex of the child, or the site or direction of the fracture. These findings may be of clinical use in the timing of corrective treatment where a leg length discrepancy exists as a result of injury to, or malunion of, a long bone in the lower limb of a child

Spontaneous correction of deformity is produced by bone remodelling during the period of growth. The purpose of this experimental study was to find out in which phase and to what extent asymmetrical epiphysial growth participated in the correction of an experimentally produced deformity. Transverse wedge osteotomy was performed in the legs of twenty growing mongrel dogs, the fragments being fixed with bent AO-plates. From radiographs taken at intervals of two weeks the epiphysial and axial angles were measured. Nine dogs were given tetracycline ten to twenty days before death and the cut surfaces were photographed in reflected ultra-violet light. It was found that epiphysial growth played an important role in the remodelling process. This factor accounted for roughly half of the total correction and averaged 12-5 degrees during the observation time of 160 days. The greatest correction occurred during the first weeks. Correction of the epiphysial angle took place with acceleration of growth

We studied the pattern of proximal femoral growth after severe Perthes' disease (Catterall grade III or IV) by retrospective analysis of serial radiographs in 52 hips (46 patients). Our aim was to determine the relationship between proximal femoral growth abnormalities and metaphyseal cysts, epiphyseal extrusion, physeal narrowing, and extensive epiphyseal necrosis. The average follow-up after treatment was 9.8 years (range 4 to 16 years), and 37 of the hips were followed to skeletal maturity. Slowing of proximal femoral growth was common: symmetrical abnormality was seen in 26 hips and asymmetrical abnormality in nine. However, definite premature closure of the proximal femoral physis was seen in only three hips. Abnormality seemed to be due to altered growth velocity rather than to bar formation in most cases. Metaphyseal cysts, epiphyseal extrusion and physeal narrowing during the active stage of the disease, alone or in combination, were found to be neither sensitive nor specific predictors of the subsequent growth pattern

The growth plates of the femoral head of Japanese white rabbits aged 5, 10, 15 and 20 weeks were stained for apoptotic and proliferating chondrocytes using the TUNEL and PCNA antibody staining techniques. Both TUNEL- and PCNA-positive chondrocytes were detected in all of the specimens. The positive ratios of both stainings were calculated for the whole plate and for the resting, proliferating and hypertrophic zones. The highest ratios in both stainings occurred in the hypertrophic zone in all age groups. With growth, the TUNEL-positive ratio increased whereas the proliferating ratio decreased. We suggest that the increase in chondrocytic death by apoptosis and the decrease in cell proliferation potential led to closure of the growth plate

We subjected the proximal tibial growth plates of six-week-old rabbits to either compression or distraction of 1 kg on both legs. On one side the proximal tibial periosteum was divided circumferentially and stripped for 1 cm. After six weeks, growth was measured at both proximal and distal growth plates. Compression inhibited total tibial growth and distraction enhanced it. The compressed growth plate grew less and the distracted growth plate grew more, but there was a reciprocal change at the other end of the bone. Periosteal division enhanced growth at the adjacent growth plate but inhibited it distally; the effect of distraction was enhanced and that of compression reduced. We found reciprocal growth rates at the proximal and distal growth plates. Relatively small amounts of compression or distraction did affect total bone growth. Periosteal division appeared to induce overgrowth at least partly by a mechanical effect; it may be useful as an adjunct to other methods of leg lengthening, though not to epiphyseolysis

We investigated the effect of bone lengthening by callotasis on longitudinal growth of the tibia in rabbits. Ninety-nine five-week-old immature rabbits were divided into five groups according to the percentage of lengthening: group I, 10%; group II, 20%; group III, 30%; group IV, 40%; and group V, sham operation without lengthening. Corticotomy was performed at the proximal metaphysis of the left tibia and the right tibia was used as a control. The lengthening rate was 0.25 mm twice daily. Radiological, histomorphometric, and immunohistochemical studies were done on animals killed at the time of corticotomy, at the completion of lengthening, and thereafter every two weeks until 12 weeks. Tibial lengthening did not cause retardation of growth when the bone was lengthened by up to 20%. When the bone was lengthened by 30% or more, growth retardation was evident, and persisted until skeletal maturity

We have measured the increase in height and width of the vertebral bodies and expressed them as percentages of the total growth in children aged 10 to 17 years. The first group, 10 boys and 10 girls, each had a single thoracic adolescent idiopathic scoliosis while the second group, 10 girls, each had a single lumbar adolescent idiopathic scoliosis. No significant differences were found between the growth increments and spinal dimensions of the vertebral bodies involved in the scoliotic curve and those vertebrae outside the curve in the same patient. The vertebrae were more slender in girls than in boys

Aims. It is increasingly appreciated that coordinated regulation of angiogenesis and osteogenesis is needed for bone formation. How this regulation is achieved during peri-implant bone healing, such as osseointegration, is largely unclear. This study examined the relationship between angiogenesis and osteogenesis in a unique model of osseointegration of a mouse tibial implant by pharmacologically blocking the vascular endothelial growth factor (VEGF) pathway. Materials and Methods. An implant was inserted into the right tibia of 16-week-old female C57BL/6 mice (n = 38). Mice received anti-VEGF receptor-1 (VEGFR-1) antibody (25 mg/kg) and VEGF receptor-2 (VEGFR-2) antibody (25 mg/kg; n = 19) or an isotype control antibody (n = 19). Flow cytometric (n = 4/group) and immunofluorescent (n = 3/group) analyses were performed at two weeks post-implantation to detect the distribution and density of CD31. hi. EMCN. hi. endothelium. RNA sequencing analysis was performed using sorted CD31. hi. EMCN. hi. endothelial cells (n = 2/group). Osteoblast lineage cells expressing osterix (OSX) and osteopontin (OPN) were also detected with immunofluorescence. Mechanical pull-out testing (n = 12/group) was used at four weeks post-implantation to determine the strength of the bone-implant interface. After pull-out testing, the tissue attached to the implant surface was harvested. Whole mount immunofluorescent staining of OSX and OPN was performed to determine the amount of osteoblast lineage cells. Results. Flow cytometry revealed that anti-VEGFR treatment decreased CD31. hi. EMCN. hi. vascular endothelium in the peri-implant bone versus controls at two weeks post-implantation. This was confirmed by the decrease of CD31 and endomucin (EMCN) double-positive cells detected with immunofluorescence. In addition, treated mice had more OPN-positive cells in both peri-implant bone and tissue on the implant surface at two weeks and four weeks, respectively. More OSX-positive cells were present in peri-implant bone at two weeks. More importantly, anti-VEGFR treatment decreased the maximum load of pull-out testing compared with the control. Conclusion. VEGF pathway controls the coupling of angiogenesis and osteogenesis in orthopaedic implant osseointegration by affecting the formation of CD31. hi. EMCN. hi. endothelium. Cite this article: Bone Joint J 2019;101-B(7 Supple C):108–114

Our aim was to evaluate the expression of transcription factors CCAAT/enhancer-binding protein-beta (C/EBP. β. ) and C/EBP-homologous protein (CHOP) in the growth plate. Proximal tibial epiphyseal growth plates from ten 15-day-old Wistar rats were used. Additionally, anti-proliferating cell nuclear antigen (PCNA), anti-5-bromo-2’-deoxyuridine (BrdU) immunostaining, terminal transferase dUTP nick end-labelling (TUNEL) and nucleolar organiser region-associated proteins (AgNOR) techniques were peformed. The histological morphology of the growth plate from C/EBP. β. knock-out mice was also analysed. The normal growth plate showed that C/EBP. β. and CHOP factors are expressed both in the germinative/ upper proliferative and in the lower proliferative zones. Furthermore, BdrU+ and PCNA+ cells were present exclusively in the germinative and proliferative zones, while TUNEL+ and AgNOR+ cells were seen in all three zones of the growth plate. Acellular areas, hypocellularity, the increase in cell death and anomalies in the architecture of the cell columns were observed in the growth plates of C/EBP. β. (−/ −) knockout mice. We suggest that C/EBP. β. and CHOP transcription factors may be key modulators participating in the chondrocyte differentiation process in the growth plate

We investigated the feasibility in the dog of using transfers of the distal ulna into the radius either as growth plate replacements or as accessory growth plates in the diaphysis. Preliminary work determined the most satisfactory method of skeletal fixation. The experimental study showed that transfers used as growth plate replacements grew at almost normal rates, uniting with the recipient bone in a mean of 7.1 weeks. Transfers into the diaphysis initially nearly doubled the growth rate of the radius, although in the long-term results were unsatisfactory, because of fracture of the graft after a mean period of 8.2 weeks

Children undergoing continuous corticosteroid therapy become stunted in height. The mechanism of this inhibition of natural growth has been investigated in the lower femoral epiphysial growth plate of young rabbits on daily corticosteroid. The growth plate became narrow: fewer cells in the germinative zone gave rise to short widely-spaced chondrocyte columns, each with a reduced number of mature and hypertrophic cells; the pattern of trabecular bone in the metaphysis was also disturbed. After even small doses these changes develop very rapidly, and therefore impose a threat to the growth of children receiving treatment with corticosteroids

Platelet-derived growth factor (PDGF) is known to stimulate osteoblast or osteoprogenitor cell activity. We investigated the effect of locally applied PDGF from poly-. d. ,l-lactide (PDLLA)-coated implants on fracture healing in a rat model. A closed fracture of the right tibia of four-month-old Sprague-Dawley rats (n = 40) was stabilised with implants coated with a biodegradable PDLLA versus implants coated with PDLLA and PDGF. Radiographs were taken throughout the study, and a marker of DNA activity, bromodeoxyuridine (BrdU), was injected before the rats were killed at three, seven and ten days. The radiographs showed consolidation of the callus in the PDGF-treated group compared with the control group at all three time points. In the PDGF-treated group, immunohistochemical staining of BrdU showed that the distribution of proliferating cells in all cellular events was higher after ten days compared with that at three and seven days. These results indicate that local application of PDGF from biodegradable PDLLA-coated implants significantly accelerates fracture healing in experimental animals. Further development may help fracture healing in the clinical situation.

1. Tetracycline labelling methods have been used to measure the rate of growth in length and the rate of growth in width of the tibia of the normal rat. 2. The main limitations of the tetracycline methods are that in very young animals the bands of labelled bone are indistinct and remodelling occurs quickly; in animals nearing maturity, the growth in width is very slow and periods of at least fourteen days are required to give reliable results. 3. The tetracycline labelling methods can be used also to determine changes in the basic processes of bone formation and bone resorption

The growth of the stump has been studied in eighteen children with below-knee amputations. Measurements were available shortly after operation and later at skeletal maturity. It was found that all patients achieved less than expected growth and that the reduction was greater in those patients who had had amputation for congenital deformity

1. Some of the factors responsible for vertebral growth have been discussed. 2. In kyphosis and scoliosis it is important to prevent progressive epiphysial damage. 3. In selected cases of progressive scoliosis, epiphysiodesis on the convex side will correct unequal growth. 4. The technique of spinal epiphysiodesis is described and the results that may be expected are discussed

Injuries to the spinal cord may be associated with increased healing of fractures. This can be of benefit, but excessive bone growth can also cause considerable adverse effects. We evaluated two groups of patients with fractures of the spinal column, those with neurological compromise (n = 10) and those without (n = 15), and also a control group with an isolated fracture of a long bone (n = 12). The level of transforming growth factor-beta (TGF-β), was measured at five time points after injury (days 1, 5, 10, 42 and 84). The peak level of 142.79 ng/ml was found at day 84 in the neurology group (p < 0.001 vs other time points). The other groups peaked at day 42 and had a decrease at day 84 after injury (p ≤ 0.001). Our findings suggest that TGF-β may have a role in the increased bone turnover and attendant complications seen in patients with acute injuries to the spinal cord

Growth plates taken from five- to 20-week-old Japanese white rabbits were immunostained for c-Myc protein. This was localised both in the proliferating zone and upper hypertrophic zone at five weeks, whereas after ten weeks it was found mostly in the lower hypertrophic zone. The proliferating chondrocytes tended to show nuclear staining and the hypertrophic cells cytoplasmic staining, although the terminal hypertrophic chondrocytes sometimes expressed the protein in their nuclei. In the younger rabbits, c-Myc co-localised with proliferating cell nuclear antigen, whereas in the hypertrophic zone of older rabbits, it was present in some chondrocytes the nuclei of which also contained DNA breaks. Our study suggests that, in the rabbit growth plate, c-Myc is associated with different cellular processes, depending on the age and the developmental stage of the chondrocytes

1. A study of the average rate of growth of the legs and trunk of 202 normal average maturing children is presented. 2. The annual growth of the limbs and trunk was related to the skeletal age of each child, and the increments of growth per skeletal year subjected to statistical analysis. 3. Methods of growth prediction of leg length and mature height have been derived and the practical application of the investigation to orthopaedic surgery is discussed

We have reviewed 15 cases of triplane fracture of the distal tibia. The mechanism of injury is lateral rotation and the anatomical pattern of the fracture depends on the state of the growth plate at the time of injury. In seven of our cases the anteromedial part of the growth plate was fused, but in eight children the plate was completely open. In six of these eight children there was a hump or projection of the medial growth plate. It is suggested that this hump stabilises the anteromedial part of the epiphysis in a manner similar to the partial anteromedial fusion seen in older children, and that this accounts for the occurrence of triplane fracture in the presence of an open growth plate

Human bone-marrow mesenchymal stem cells have an important role in the repair of musculoskeletal tissues by migrating from the bone marrow into the injured site and undergoing differentiation. We investigated the use of autologous human serum as a substitute for fetal bovine serum in the ex vivo expansion medium to avoid the transmission of dangerous transfectants during clinical reconstruction procedures. Autologous human serum was as effective in stimulating growth of bone-marrow stem cells as fetal bovine serum. Furthermore, medium supplemented with autologous human serum was more effective in promoting motility than medium with fetal bovine serum in all cases. Addition of B-fibroblast growth factor to medium with human serum stimulated growth, but not motility. Our results suggest that autologous human serum may provide sufficient ex vivo expansion of human bone-marrow mesenchymal stem cells possessing multidifferentiation potential and may be better than fetal bovine serum in preserving high motility

A self-control ratio, the spine-pelvis index (SPI), was proposed for the assessment of patients with adolescent idiopathic scoliosis (AIS) in this study. The aim was to evaluate the disproportionate growth between the spine and pelvis in these patients using SPI. A total of 64 female patients with thoracic AIS were randomly enrolled between December 2010 and October 2012 (mean age 13 years, standard deviation (. sd. ) 2.17; 9 to 18) and a further 73 healthy female patients with a mean age of 12.4 years (mean age 12.4 years, . sd. 2.24; 9 to 18), were randomly selected from a normal control database at our centre. The radiographic parameters measured included length of spine (LOS), height of spine (HOS), length of thoracic vertebrae (LOT), height of thoracic vertebrae (HOT), width of pelvis (WOP), height of pelvis (HOP) and width of thorax (WOT). SPI was defined as the ratio LOS/HOP. The SPI and LOT/HOP in patients with AIS showed a significant increase when compared with normal girls (p < 0.001 and p < 0.001 respectively), implying an abnormal pattern of growth of the spine relative to the pelvis in patients with AIS. . No significant difference in SPI was found in different age groups in the control group, making the SPI an age-independent parameter with a mean value of 2.219 (2.164 to 2.239). We also found that the SPI was not related to maturity in the control group. . This study, for the first time, used a self-control ratio to confirm the disproportionate patterns of growth of the spine and pelvis in patients with thoracic AIS, highlighting that the SPI is not affected by age or maturity. Cite this article: Bone Joint J 2015;97-B:1668–74

Chondrocytes of the growth plate are generally assumed to undergo apoptosis, but the mechanisms which induce this cell death are not known. The Fas receptor is a mediator of the apoptotic signal in some systems. We studied its expression in situ in growth plates of rabbits aged from five to 20 weeks. In addition, we investigated the immunolocalisation in the growth plates of the bone proteins, osteonectin and osteocalcin, and the changes in their expression with age. The Fas-positive chondrocytes were found mostly in the hypertrophic zone, as were the osteonectin-positive and osteocalcin-positive cells. The percentage of Fas-positive cells increased with age whereas little change was found in the number of osteonectin-positive and osteocalcin-positive chondrocytes. Many of the Fas-positive chondrocytes were also TUNEL-positive. This strongly suggests that apoptosis in the growth plate is mediated through the Fas system. Double immunostaining for osteocalcin and Fas showed that not all hypertrophic chondrocytes were of the same cell type. Some chondrocytes stained for osteocalcin only, others for Fas only, while some were positive for both

A model was developed in the dog to allow both the metaphysis and epiphysis of the distal ulnar growth plate to be microsurgically revascularised from the pedicle of the anterior interosseous vessels. With both circulations revascularised, grafts retained their structural integrity and growth continued at rates only slightly less than normal (mean 85%). If either or both circulations were not revascularised, growth rates were lower and were associated with skeletal collapse in the ischaemic bone segment

We report 21 cases of stress injury of the distal radial growth plate-occurring in gymnasts before skeletal maturity. The injury appears to be caused by inability of the growth plate to withstand rotational and compressive forces. Our observations have confirmed that the skeletal age of gymnasts is retarded, which increases the length of time during which the epiphysis is at risk of damage

1. As previous experiments with autogenous transplantation of epiphysial growth plates have given limited success, a study was carried out on two groups of rabbits, one of which was given hyperbaric oxygen post-operatively in an attempt to improve the results. 2. Sixty-four New Zealand white rabbits had the distal ulnar growth plate transplanted from left to right and vice versa, giving a total of 128 transplants. 3. In the group of thirty-two rabbits given hyperbaric oxygen 48 per cent of the transplants were regarded as successful when examined histologically six weeks after operation, while in the control group the figure was 28 per cent. 4. This investigation suggests the clinical use of hyperbaric oxygen to improve the results of transplantation of growth cartilage

Growth at the proximal tibial epiphyseal plate of the rat has been measured following three different growth-stimulating procedures. These were proximal periosteal release, distal periosteal release and full periosteal stripping of the diaphysis. A new radiographic method using a photographic technique has made it possible to take accurate measurements of the rate of long-bone growth in small experimental animals. From the results of this animal series we conclude that proximal tibial periosteal division is likely to be the most effective of the three procedures when used to correct leg-length discrepancy in the growing child

Synthetic bone substitutes provide an alternative to autograft but do not give equivalent clinical results. Their performance may be enhanced by adding osteogenic growth factors. In this study, TGFβ1 was absorbed on to a carrier of β tricalcium phosphate and Gelfoam® and used to fill a defect around a tibial implant in a rat model of revision arthoplasty. We added 0.0, 0.02 μg, 0.1 μg or 1.0 μg of TGFβ1 to the carrier and then implanted it around an hydroxyapatite-coated stainless-steel pin in the proximal tibia of rats. The tibiae were harvested at three, six or 26 weeks and the amount of bone formation and ceramic resorption were assessed. TGFβ1 had no effect on the amount of bone in the defect, the amount of fluorescent label incorporated or the rate of mineral apposition. The growth factor did not significantly affect the amount of β TCP remaining in the tissue at any of the time points

Platelet-rich plasma is a new inductive therapy which is being increasingly used for the treatment of the complications of bone healing, such as infection and nonunion. The activator for platelet-rich plasma is a mixture of thrombin and calcium chloride which produces a platelet-rich gel. We analysed the antibacterial effect of platelet-rich gel in vitro by using the platelet-rich plasma samples of 20 volunteers. In vitro laboratory susceptibility to platelet-rich gel was determined by the Kirby-Bauer disc-diffusion method. Baseline antimicrobial activity was assessed by measuring the zones of inhibition on agar plates coated with selected bacterial strains. Zones of inhibition produced by platelet-rich gel ranged between 6 mm and 24 mm (mean 9.83 mm) in diameter. Platelet-rich gel inhibited the growth of Staphylococcus aureus and was also active against Escherichia coli. There was no activity against Klebsiella pneumoniae, Enterococcus faecalis, and Pseudomonas aeruginosa. Moreover, platelet-rich gel seemed to induce the in vitro growth of Ps. aeruginosa, suggesting that it may cause an exacerbation of infections with this organism. We believe that a combination of the inductive and antimicrobial properties of platelet-rich gel can improve the treatment of infected delayed healing and nonunion

Twenty-four children with infantile or juvenile idiopathic scoliosis had their spines corrected and solidly fused posteriorly before the age of eleven years. The growth of the fusion area was then accurately measured for a mean of 4.5 years during the adolescent growth spurt. During this period all longitudinal growth in the posterior elements ceased. The vertebral bodies continued to grow anteriorly, but the thick posterior fusion prevented the development of a lordosis. Initially the anterior growth was accommodated by narrowing of the intervertebral disc spaces, but eventually the vertebral bodies bulged laterally towards the convexity and pivoted on the posterior fusion, giving rise to loss of correction, increasing vertebral rotation and recurrence of the rib hump

We performed intra-articular reconstruction of the anterior cruciate ligament (ACL) with the semitendinosus tendon placed in 2 mm diameter tunnels in 21 skeletally immature rabbits. The operation caused 11% damage to the physis of the femur on the frontal plane and 3% of its cross-sectional area but no alteration of growth or axial deviation of the bone resulted. In the tibia, the operation caused 12% damage to the physis in the frontal plane and 4% of the cross-sectional area. Two tibiae developed valgus deformities and one was shortened. Histological examination showed no areas of epiphysiodesis. There was no abnormality of growth-plate thickness in the two cases of tibia valga. Osseous metaplasia in the grafted tendons did not occur. The results suggest the need for careful evaluation of the percentage of damage to the growth plate before using intra-articular methods for reconstruction of the anterior cruciate ligament in adolescents

We studied the presence of anabolic growth factors in human herniated intervertebral discs (IVD) using a reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. Messenger RNA (mRNA) was isolated from the nucleus pulposus using oligo (dT). 25. superparamagnetic beads and probing with gene-specific primers in RT-PCR. mRNA coding for TGF-α (3/10), EGF (0/10), TGF-β1 (0/10) and TGF-β3 (2/10) or the EGF receptor (EGF-R; 0/10) and TGF-β type-II receptor (0/10) was found only occasionally. Beta-actin was always present and positive sample controls confirmed the validity of the RT-PCR assay. These RT-PCR findings were confirmed using immunohistochemical staining of EGF and TFG-β, whereas TGF-α protein was always found associated with discocytes. We conclude that the nucleus pulposus of the herniated IVD is vulnerable to proteolytic degradation and depletion of proteoglycans due to the lack and/or low production of anabolic growth factors/receptors which could increase the local synthesis of the extracellular matrix

1. Analyses are presented of comparable groups of the two commonest bone-forming tumours—osteochondroma and osteogenic sarcoma—derived from the following sources: Bristol Bone Tumour Register; British Empire Cancer Campaign Annual Report (1949); Stocks and Barrington (1925); Meyerding (1927); and Geschickter and Copeland (1949). 2. From this study, the following features emerge as characteristic and common to both tumours. 1) Both tumours are commoner in the male during the age periods 0-34 years, and over fifty years, with the possible exceptions of tumours of the humerus during early life and tumours of the pelvis. 2) The male preponderance is most marked for the appendicular long bones. 3) The male preponderance is greatest during the age period 15-34 years. 4) In the separate bones, these tumours tend to arise at a somewhat earlier age in the female. 5) In both sexes both tumours tend to arise at an earlier age in the bones of the upper arm and shoulder girdle than in those of the lower limb and pelvis. 6) Both tumours are related to an aberration of endochondral growth in length of bone. 3. The greater growth of the male, and differences in skeletal development in the two sexes, offer a simple and reasonably consistent explanation of these peculiarities and make it possible to discern the interplay of the three factors of age, sex and site of origin of the tumour. 4. From this concept it is possible to make a crude estimate of the factors of time and bulk of tissue which when combined may well account for the observed male preponderance of these tumours, and their anatomical distribution

Aims

Temporary epiphysiodesis (ED) is commonly applied in children and adolescents to treat leg length discrepancies (LLDs) and tall stature. Traditional Blount staples or modern two-hole plates are used in clinical practice. However, they require accurate planning, precise surgical techniques, and attentive follow-up to achieve the desired outcome without complications. This study reports the results of ED using a novel rigid staple (RigidTack) incorporating safety, as well as technical and procedural success according to the idea, development, evaluation, assessment, long-term (IDEAL) study framework.

In 65 mature Wistar rats a Kirschner wire was introduced into the medullary cavity of each femur. A closed transverse mid-shaft fracture of one femur was produced by a three-point bending technique. Subsequently the mechanical characteristics of the healing fracture, including the torque and angle of twist required to take the callus to its yield point and to ultimate failure, were compared with those for the opposite femur of each rat. Controls were killed in groups at two, three, four, five and seven weeks. Test animals were given bovine growth hormone in a daily dose of five milligrams before being killed in groups at two, three and four weeks. A significant increase in torque index was found in the two-week group of test animals but not in subsequent groups. No evidence was found that growth hormone given alone could produce an overall shortening of the healing time in fresh fractures

A total of 25 children (37 legs and 51 segments) with coronal plane deformities around the knee were treated with the extraperiosteal application of a flexible two-hole plate and screws. The mean age was 11.6 years (5.5 to 14.9), the median angle of deformity treated was 8.3° and mean time for correction was 16.1 months (7 to 37.3). There was a mean rate of correction of 0.7° per month in the femur (0.3° to 1.5°), 0.5° per month in the tibia (0.1° to 0.9°) and 1.2° per month (0.1° to 2.2°) if femur and tibia were treated concurrently. Correction was faster if the child was under 10 years of age (p = 0.05). The patients were reviewed between six and 32 months after plate removal. One child had a rebound deformity but no permanent physeal tethers were encountered. The guided growth technique, as performed using a flexible titanium plate, is simple and safe for treating periarticular deformities of the leg

1. A method is described of demonstrating in vivo the utilisation of radioactive sulphur. 35. and of radioactive phosphorus. 32. during bone growth and repair. 2. The relationship between labelled chondroitin sulphuric acid and labelled phosphate complexes has been studied, the importance and significance of vascularity and the localisation of the enzyme alkaline phosphatase being noted. 3. It was found that bone growth by external accretion, both epiphysial and periosteal, was accompanied by an increased utilisation of radioactive chondroitin sulphuric acid and calcium phosphate complexes. 4. During repair in a fracture site, although there was deposition of radioactive phosphate, no preferential localisation of radioactive sulphur was observed and the possible explanations of this are discussed

This prospective study of 136 children with progressive infantile scoliosis treated under the age of four years, and followed up for nine years, shows that the scoliosis can be reversed by harnessing the vigorous growth of the infant to early treatment by serial corrective plaster jackets. In 94 children (group 1), who were referred and treated in the early stages of progression, at a mean age of one year seven months (6 to 48 months) and with a mean Cobb angle of 32° (11° to 65°), the scoliosis resolved by a mean age of three years and six months. They needed no further treatment and went on to lead a normal life. At the last follow-up, their mean age was 11 years and two months (1 year 10 months to 25 years 2 months), 23 (24.5%) were at Risser stages 4 and 5 and 13 girls were post-menarchal. In 42 children (group 2), who were referred late at a mean age of two years and six months (11 to 48 months) and with a mean Cobb angle of 52° (23° to 92°), treatment could only reduce but not reverse the deformity. At the last follow-up, at a mean age of ten years and four months (1 year 9 months to 22 years 1 month), eight children (19%) were at Risser stages 4 and 5 and five girls were post-menarchal. Fifteen children (35.7%) had undergone spinal fusion, as may all the rest eventually

1. A case is reported of a girl aged fifteen with growth hormone deficiency who developed a slip of the left femoral capital epiphysis at the age of seventeen during human growth hormone therapy. 2. The epiphysiolysis is regarded as iatrogenic

We undertook a prospective study to evaluate the prognostic significance of the serum levels of vascular endothelial growth factor (VEGF) in predicting the survival of patients with osteosarcoma. The levels were measured by an enzyme-linked immunosorbent assay in 15 patients with osteosarcoma before commencing treatment. The patients were divided into two groups, with a high or a low serum VEGF level, and the incidence of metastases and overall survival rate were compared. No significant relationship was observed between the serum VEGF levels and gender, age, the size of the tumour or the response to pre-operative chemotherapy. Patients with a serum VEGF > 1000 pg/ml had significantly worse survival than those with a level < 1000 pg/ml (p = 0.002). The serum VEGF level may be useful in predicting the prognosis for survival in patients with osteosarcoma

Bone growth into cementless prosthetic components is compromised by osteoporosis, by any gap between the implant and the bone, by micromotion, and after the revision of failed prostheses. Recombinant human transforming growth factor-β1 (rhTGF-β1) has recently been shown to be a potent stimulator of bone healing and bone formation in various models in vivo. We have investigated the potential of rhTGF-β1, adsorbed on to weight-loaded tricalcium phosphate (TCP) coated implants, to enhance bone ongrowth and mechanical fixation. We inserted cylindrical grit-blasted titanium alloy implants bilaterally into the weight-bearing part of the medial femoral condyles of ten skeletally mature dogs. The implants were mounted on special devices which ensured stable weight-loading during each gait cycle. All implants were initially surrounded by a 0.75 mm gap and were coated with TCP ceramic. Each animal received two implants, one with 0.3 μg rhTGF-β1 adsorbed on the ceramic surface and the other without growth factor. Histological analysis showed that bone ongrowth was significantly increased from 22 ± 5.6% bone-implant contact in the control group to 36 ± 2.9% in the rhTGF-β stimulated group, an increase of 59%. The volume of bone in the gap was increased by 16% in rhTGF-β1-stimulated TCP-coated implants, but this difference was not significant. Mechanical push-out tests showed no difference in fixation of the implant between the two groups. Our study suggests that rhTGF-β1 adsorbed on TCP-ceramic-coated implants can enhance bone ongrowth

We reviewed 14 patients (16 hips) treated by open reduction and upper femoral derotation osteotomy for congenital dislocation of the hip. Nine patients with 11 treated hips had growth deformities of the proximal femur; in all of them the top screw of the fixation plate lay within the cartilaginous precursor of the greater trochanter. In the five control hips the top screw was more distal. In the nine patients (mean follow-up 10.8 years) there was an increase of 14 degrees in the neck-shaft angle (p = 0.01) and of 18 degrees in the angle between the capital femoral physis and the shaft (p = 0.01) compared to the control group. This indicates that growth disturbance of the greater trochanteric apophysis as a result of plate fixation leads to long-term deformity

A review is presented of 13 young patients with congenital scoliosis who were treated by epiphysiodesis of part of the vertebral bodies combined with posterior fusion, both on the convex side; the plan was to arrest growth on the convexity which, combined with growth of the concave side, would result in progressive correction of the curve. The first patient was operated on at the age of four years and has now reached skeletal maturity with complete correction of her curve. Several others, still growing, are showing progressive correction. Only three curves, in which kyphosis was more severe than scoliosis, have deteriorated since operation. Although full assessment must await skeletal maturity of all the patients, this approach appears to have sufficient potential to justify an early report

Assessment of skeletal age is important in children’s orthopaedics. We compared two simplified methods used in the assessment of skeletal age. Both methods have been described previously with one based on the appearance of the epiphysis at the olecranon and the other on the digital epiphyses. We also investigated the influence of assessor experience on applying these two methods. Our investigation was based on the anteroposterior left hand and lateral elbow radiographs of 44 boys (mean: 14.4; 12.4 to 16.1 ) and 78 girls (mean: 13.0; 11.1 to14.9) obtained during the pubertal growth spurt. A total of nine observers examined the radiographs with the observers assigned to three groups based on their experience (experienced, intermediate and novice). These raters were required to determined skeletal ages twice at six-week intervals. The correlation between the two methods was determined per assessment and per observer groups. Interclass correlation coefficients (ICC) evaluated the reproducibility of the two methods. The overall correlation between the two methods was r = 0.83 for boys and r = 0.84 for girls. The correlation was equal between first and second assessment, and between the observer groups (r ≥ 0.82). There was an equally strong ICC for the assessment effect (ICC ≤ 0.4%) and observer effect (ICC ≤ 3%) for each method. There was no significant (p < 0.05) difference between the levels of experience. The two methods are equally reliable in assessing skeletal maturity. The olecranon method offers detailed information during the pubertal growth spurt, while the digital method is as accurate but less detailed, making it more useful after the pubertal growth spurt once the olecranon has ossified. Cite this article: Bone Joint J 2014;3:1556–60

The proximal fibular epiphysis was transferred in young puppies using microvascular techniques. The study demonstrated, as have previous investigators, that free epiphysial transfer without vascular anastomosis results in death of the chondrocytes of the growth plate. Histologically, the chondrocytes do not take up labelled proline, indicating diminished metabolic activity; do not take up radioactive thymidine, indicating that they are not dividing; and there is eventual disruption of the normal histological picture. In contrast, where the microvascular anastomoses re-established the blood supply to the growth plate, the epiphyses demonstrated normal histological appearance, uptake of radioactive proline and thymidine and continued to grow but at a slightly diminished rate. It is concluded that continued growth can occur after free vascularised epiphysial transfer in the dog

The cavities left after resection of bone bridges for partial closure of growth plates in children have commonly been filled with free fat grafts. Such cavities have been seen to elongate and thus enlarge during growth after the operation, but the fate of the grafts has been unknown. Similar cavities, made in the tibiae of growing pigs were filled with autogenous fat and studied by radiography for periods of up to 9 1/2 months. These cavities elongated in a manner similar to those in the clinical cases, and histological section showed them to be filled with living adipose tissue. The volume of this tissue had continuously increased in parallel with the growth in length of the bone. The fate of the grafts used in children may be similar to that seen experimentally

We reviewed 26 fractures involving the distal physis of the tibia to identify the patterns of formation and displacement of the subsequent growth disturbance lines. Twenty-one patients showed a regular "normal" pattern of line and healed with no deformity. Three patients had medical physeal arrest revealed by abnormal lines. Two other cases had a minor central physeal arrest without subsequent deformity. The pattern and character of the growth disturbance line can provide an early warning of potential deformity

The effect of early fusion on growth of the spine has been studied in rabbits. Free periosteal grafts from the tibia were transplanted either posteriorly between the spinous and articular processes or postero-laterally between the articular and transverse processes. Sound bony fusion was achieved in both the thoracic and the lumbar spine. Spinal fusion caused local narrowing and wedging of the intervertebral spaces, followed by retardation of growth and wedging of the vertebrae. A progressive structural scoliosis developed after unilateral postero-lateral fusion and a lordosis developed after posterior fusion

We have studied in vitro the effect of a hydroxyapatite (HA) tricalcium phosphate material coated with hepatocyte growth factor (HA-HGF) on cell growth, collagen synthesis and secretion of metalloproteinases (MMPs) by human osteoblasts. Cell proliferation was stimulated when osteoblasts were incubated with untreated HA and was further increased after exposure to HA-HGF. The uptake of [. 3. H]-proline was increased after treatment with HA. When osteoblasts were exposed to HA-HGF, collagen synthesis was increased with respect to HA. The secretion of MMPs in control cells was undetectable, but in HA and HA-HGF cells MMP 2 and MMP 9 were clearly synthesised. Our results suggest that HA can promote osteoblast activity and that HGF can further increase its bioactivity

1. In young rabbits the muscle belly of the tibialis anterior was marked at intervals, either on its surface with indian ink, or in its substance by wires. The intervals between ink marks were measured directly, and those between wires by radiography. After four to seven months the measurements were repeated and the amount and site of longitudinal growth determined. The experiments showed that it occurred fairly evenly throughout the length of the muscle belly. 2. By transfer of the tibialis anterior in front of the crural ligament in young rabbits its course was reduced and the extent of contraction necessary to dorsiflex the foot was increased. The rabbits were killed when fully grown and the lengths of the tendons and muscle bellies of the tibialis anterior of the normal and experimental legs were compared. It was found that in every case the tendon of the experimental muscle was shortened and its belly lengthened in comparison with the normal. It is suggested that the increased length of the muscle belly was determined by the increased distance which it had to contract in order to dorsiflex the foot

We describe the reconstruction of a defect of the medial malleolus which was the result of an accident in a ten-year-old child. A graft from the iliac crest, with the apophyseal cartilage and perichondrium, was used for reconstruction of the medial malleolus, the growth plate and the adjacent metaphyseal defect, respectively. The soft-tissue defect was covered with a free scapular flap with microvascular anastomosis. Three years after the injury stability of the ankle is excellent with adequate growth of the reconstructed epiphyseal plate

1. The authors have found epiphysial stapling a satisfactory and helpful procedure for correction of limb length discrepancy and recommend its use as described. 2. The use of a spring caliper for absolute radiographic location of the epiphysial plates and the use of two Vitallium staples each side is recommended. 3. Suggestions for avoiding injury to the epiphyses are outlined. 4. The experience of stapling operations in seventy children is reported. Forty-four of these patients have completed growth

We have investigated in vitro the release kinetics and bioactivity of fibroblast growth factor-2 (FGF-2) released from a carrier of fibrin sealant. In order to evaluate the effects of the FGF-2 delivery mechanism on the repair of articular cartilage, full-thickness cylindrical defects, 5 mm in diameter and 4 mm in depth, which were too large to undergo spontaneous repair, were created in the femoral trochlea of rabbit knees. These defects were then filled with the sealant. Approximately 50% of the FGF-2 was released from the sealant within 24 hours while its original bioactivity was maintained. The implantation of the fibrin sealant incorporating FGF-2 successfully induced healing of the surface with hyaline cartilage and concomitant repair of the subchondral bone at eight weeks after the creation of the defect. Our findings suggest that this delivery method for FGF-2 may be useful for promoting regenerative repair of full-thickness defects of articular cartilage in humans

We have reviewed the notes and radiographs of 57 patients with fractures of the proximal humeral epiphysis and examined 30 of them at 2 to 8 years after injury. Regardless of treatment the maximum shortening of the humerus was 2 cm and residual varus angulation was insignificant. Manipulation of a displaced, fresh fracture did not improve the final outcome with respect to humeral growth or function; and open reduction is very rarely indicated