Regenerating Critical Size Rat Segmental Bone Defects with a Self-Healing Hybrid Nanocomposite Hydrogel: Effect of Bone Condition and BMP-2 Incorporation.

The aim of the current study is to assess the biological performance of self-healing hydrogels based on calcium phosphate (CaP) nanoparticles and bisphosphonate (BP) conjugated hyaluronan (HA) in a critical size segmental femoral bone defect model in rats. Additionally, these hydrogels are loaded with bone morphogenetic protein 2 (BMP-2) and their performance is compared in healthy and osteoporotic bone conditions. Treatment groups comprise internal plate fixation and placement of a PTFE tube containing hydrogel (HABP -CaP) or hydrogel loaded with BMP-2 in two dosages (HABP -CaP-lowBMP2 or HABP -CaP-highBMP2). Twelve weeks after bone defect surgery, bone formation is analyzed by X-ray examination, micro-CT analysis, and histomorphometry. The data show that critical size, segmental femoral bone defects cannot be healed with HABP -CaP gel alone. Loading of the HABP -CaP gel with low dose BMP-2 significantly improve bone formation and resulted in defect bridging in 100% of the defects. Alternatively, high dose BMP-2 loading of the HABP -CaP gel does not improve bone formation within the defect area, but leads to excessive bone formation outside the defect area. Bone defect healing is not affected by osteoporotic bone conditions.

Bone Regeneration in Critical-Sized Bone Defects Treated with Additively Manufactured Porous Metallic Biomaterials: The Effects of Inelastic Mechanical Properties.

Additively manufactured (AM) porous metallic biomaterials, in general, and AM porous titanium, in particular, have recently emerged as promising candidates for bone substitution. The porous design of such materials allows for mimicking the elastic mechanical properties of native bone tissue and showed to be effective in improving bone regeneration. It is, however, not clear what role the other mechanical properties of the bulk material such as ductility play in the performance of such biomaterials. In this study, we compared the bone tissue regeneration performance of AM porous biomaterials made from the commonly used titanium alloy Ti6Al4V-ELI with that of commercially pure titanium (CP-Ti). CP-Ti was selected because of its high ductility as compared to Ti6Al4V-ELI. Critical-sized (6 mm diameter) femoral defects in rats were treated with implants made from both Ti6Al4V-ELI and CP-Ti. Bone regeneration was assessed up to 11 weeks using micro-CT scanning. The regenerated bone volume was assessed ex vivo followed by histology and biomechanical testing to assess osseointegration of the implants. The bony defects treated with AM CP-Ti implants generally showed higher volumes of regenerated bone as compared to those treated with AM Ti6Al4V-ELI. The torsional strength of the two titanium groups were similar however, and both considerably lower than those measured for intact bony tissue. These findings show the importance of material type and ductility of the bulk material in the ability for bone tissue regeneration of AM porous biomaterials.

Effect of unfocused extracorporeal shockwave therapy on bone mineral content of twelve distal forearms of postmenopausal women: a clinical pilot study.

Extracorporeal shockwave therapy showed a pronounced effect on bone mass in previous animal studies. We showed in this pilot study that a single treatment with unfocused shockwave therapy in unselected patients does not show side effects. Although our study did not show any effect of shockwave on BMD, the limited sample size does not definitively exclude this and a study with 174 subjects per group would be needed to show an effect size of 0.3 with a power of 80%. PURPOSE: Unfocused extracorporeal shockwave therapy might stimulate bone formation to reduce the fracture risk. In this study, we assessed the safety of unfocused extracorporeal shockwave therapy and its effects on bone mass. METHODS: A clinical pilot study with twelve female patients free of bone disease undergoing elective surgery of the lower extremity or elective spinal surgery under general anesthesia received 3.000 electrohydraulic-generated unfocused extracorporeal shockwaves (energy flux density 0.3 mJ/mm2) to one distal forearm. The contralateral forearm served as a control. We examined the effect on bone mass with the use of repeated dual energy X-ray absorptiometry measurements and we measured patient discomfort around the therapy. RESULTS: No difference in bone mineral content and density was measured 6 and 12 weeks after therapy. shockwave therapy occasionally caused transient erythema or mild hematoma, but no discomfort in daily life or (late) adverse events. CONCLUSIONS: Unfocused extracorporeal shockwave therapy is a safe treatment, but no increase in bone mass on the forearm was found at 0.3 mJ/mm2 energy flux density. In this study, we were not able to demonstrate that a single treatment with unfocused shockwave therapy in unselected patients had any effect in terms of bone mineral density (BMD) or bone mineral content (BMC). A power analysis indicated that 174 patients per group are required to show an effect size of 0.3 with a power of 80%.

Unfocused shockwaves for osteoinduction in bone substitutes in rat cortical bone defects.

Bone substitutes are frequently used in clinical practice but often exhibit limited osteoinductivity. We hypothesized that unfocused shockwaves enhance the osteoinductivity of bone substitutes and improve osteointegration and angiogenesis. Three different bone substitutes, namely porous tricalcium phosphate, porous hydroxyapatite and porous titanium alloy, were implanted in a critical size (i.e. 6-mm) femoral defect in rats. The femora were treated twice with 1500 shockwaves at 2 and 4 weeks after surgery and compared with non-treated controls. The net volume of de novo bone in the defect was measured by microCT-scanning during 11-weeks follow-up. Bone ingrowth and angiogenesis in the bone substitutes was examined at 5 and 11 weeks using histology. It was shown that hydroxyapatite and titanium both had an increase of bone ingrowth with more bone in the shockwave group compared to the control group, whereas resorption was seen in tricalcium phosphate bone substitutes over time and this was insensitive to shockwave treatment. In conclusion, hydroxyapatite and titanium bone substitutes favour from shockwave treatment, whereas tricalcium phosphate does not. This study shows that osteoinduction and osteointegration of bone substitutes can be influenced with unfocused shockwave therapy, but among other factors depend on the type of bone substitute, likely reflecting its mechanical and biological properties.

Optimization of screw fixation in rat bone with extracorporeal shock waves.

Screw fixation in osteoporotic patients is becoming an increasing problem in orthopaedic surgery as deterioration of cortical and cancellous bone hamper biomechanical stability and screw fixation. This might result in delayed weight-bearing or failure of instrumentation. We hypothesized that local peri-operative shock wave treatment can optimize osseointegration and subsequent screw fixation. In eight female Wistar rats, two cancellous and two cortical bone screws were implanted in both femora and tibiae. Immediately after implantation, 3.000 unfocused extracorporeal shock waves (energy flux density 0.3 mJ/mm2 ) were applied to one side. The other side served as non-treated internal control. Evaluation of osseointegration was performed after 4 weeks with the use of microCT scanning, histology with fluorochrome labeling, and pull-out tests of the screws. Four weeks after extracorporeal shock wave treatment, treated legs exhibited increased bone formation and screw fixation around cortical screws as compared to the control legs. This was corroborated by an increased pull-out of the shock wave treated cortical screws. The cancellous bone screws appeared not to be sensitive for shock wave treatment. Formation of neocortices after shock wave therapy was observed in three of eight animals. Furthermore, de novo bone formation in the bone marrow was observed in some animals. The current study showed bone formation and improved screw fixation as a result of shock wave therapy. New bone was also formed at locations remote from the screws, hence, not contributing to screw fixation. Further, research is warranted to make shock wave therapy tailor-made for fracture fixation. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:76-84, 2018.

Multiple osteochondromas (MO) in the forearm: a 12-year single-centre experience.

Multiple osteochondromas (MO) are a rare autosomal dominant disorder characterized by the presence of osteochondromas located on the long bones and axial skeleton. Patients present with growth disturbances and angular deformities of the long bones as well as limited motion of affected joints. Forearm involvement is found in a considerable number of patients and may vary from the presence of a simple osteochondroma to severe forearm deformities and radial head dislocation. Patients encounter a variety of problems and symptoms e.g., pain, functional impairment, loss of strength and cosmetic concerns. Several surgical procedures are offered from excision of symptomatic osteochondromas to challenging reconstructions of forearm deformities. We describe visualizing, planning and treating these forearm deformities in MO and, in particular, a detailed account of the surgical correction of Masada type I and Masada type II MO forearm deformities.

Complex forearm deformities: operative strategy in posttraumatic pathology.

Complex posttraumatic forearm deformities have a significant impact on the integrity of the upper extremity leading to pain, instability in both the proximal and/or distal radioulnar articulation, and reduced range of forearm motion. Corrective osteotomy or more advanced procedures for malunited fractures or other posttraumatic deformities of the upper extremity, especially in the forearm are challenging procedures. In this review we will discuss the essential aspects of anatomy and pathomechanics, clinical and radiological assessment and the pathway from preoperative planning to the actual deformity correction surgery, either with one-stage correction or using gradual lengthening with external fixation ("callotasis techniques") and finally the functional outcome we can expect for our patients. In addition we will analyze the modern computer-assisted techniques available to date.

Valvular abnormalities detected by echocardiography in 5-year survivors of childhood cancer: a long-term follow-up study.

PURPOSE: To determine the prevalence of valvular abnormalities after radiation therapy involving the heart region and/or treatment with anthracyclines and to identify associated risk factors in a large cohort of 5-year childhood cancer survivors (CCS). METHODS AND MATERIALS: The study cohort consisted of all 626 eligible 5-year CCS diagnosed with childhood cancer in the Emma Children's Hospital/Academic Medical Center between 1966 and 1996 and treated with radiation therapy involving the heart region and/or anthracyclines. We determined the presence of valvular abnormalities according to echocardiograms. Physical radiation dose was converted into the equivalent dose in 2-Gy fractions (EQD2). Using multivariable logistic regression analyses, we examined the associations between cancer treatment and valvular abnormalities. RESULTS: We identified 225 mainly mild echocardiographic valvular abnormalities in 169 of 545 CCS (31%) with a cardiac assessment (median follow-up time, 14.9 years [range, 5.1-36.8 years]; median attained age 22.0 years [range, 7.0-49.7 years]). Twenty-four CCS (4.4%) had 31 moderate or higher-graded abnormalities. Most common abnormalities were tricuspid valve disorders (n=119; 21.8%) and mitral valve disorders (n=73; 13.4%). The risk of valvular abnormalities was associated with increasing radiation dose (using EQD2) involving the heart region (odds ratio 1.33 per 10 Gy) and the presence of congenital heart disease (odds ratio 3.43). We found no statistically significant evidence that anthracyclines increase the risk. CONCLUSIONS: Almost one-third of CCS treated with potentially cardiotoxic therapy had 1 or more asymptomatic, mostly mild valvular abnormalities after a median follow-up of nearly 15 years. The most important risk factors are higher EQD2 to the heart region and congenital heart disease. Studies with longer follow-up are necessary to investigate the clinical course of asymptomatic valvular abnormalities in CCS.

Two patients with cryptococcal meningitis and idiopathic CD4 lymphopenia: defective cytokine production and reversal by recombinant interferon- gamma therapy.

BACKGROUND: Although Cryptococcus neoformans is a fungal pathogen that causes human disease predominantly in the immunocompromised host, severe cryptococcal infections are occasionally encountered in apparently immunocompetent individuals. Activation of cellular immunity by proinflammatory cytokines plays a central role in anticryptococcal defense. METHODS: We describe 2 patients with severe cryptococcal meningitis who appeared to have idiopathic CD4 lymphopenia. For these patients and for 4 healthy volunteers, ex vivo stimulation of whole blood with microbial stimuli was used to investigate putative defects in cytokine production capacity. RESULTS: Assessment of the cytokine released from the 2 patients with CD4 lymphopenia revealed a defective production of the proinflammatory cytokines interferon (IFN)- gamma and tumor necrosis factor (TNF) but not of the anti-inflammatory cytokine interleukin-10 (IL-10). One patient with disease progression despite receipt of antifungal treatment was administered immunotherapy with recombinant IFN- gamma . Administration of recombinant IFN- gamma resulted in both restoration of immunological parameters and a sustained clinical recovery. CONCLUSIONS: Refractory meningitis may be due to defective TNF and IFN- gamma production, and IFN- gamma treatment may be useful in patients with an impaired cellular immune response and refractory cryptococcal meningitis.

Cytogenetic and molecular analysis of early stage renal cell carcinomas in a family with a translocation (2;3)(q35;q21).

Previously, we described a family with renal cell carcinoma (RCC) and a constitutional balanced t(2;3) (q35;q21). Based on loss of heterozygosity and von Hippel-Lindau (VHL) gene mutation analyses in five tumor biopsies from three patients in this family, we proposed a multistep model for RCC development in which the familial translocation may act as a primary oncogenic event leading to (nondisjunctional) loss of the translocation-derived chromosome 3, and somatic mutation of the VHL gene as a secondary event related to tumor progression. Here, we describe the cytogenetic and molecular analysis of three novel tumors at early stages of development in two members of this family. Again, loss of derivative chromosome 3 was found in two of these tumors and a VHL mutation in one of them. In the third tumor, however, none of these abnormalities could be detected. These results underline our previous notion that loss of derivative chromosome 3 and VHL gene mutation play critical roles in familial RCC. In addition, they show that both anomalies may occur at relatively early stages of tumor development.