Andras Heijink

Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration

Bone regeneration is a coordinated cascade of events regulated by several cytokines and growth factors. Angiogenic growth factors are predominantly expressed during the early phases for re-establishment of the vascularity, whereas osteogenic growth factors are continuously expressed during bone formation and remodeling. Since vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs) are key regulators of angiogenesis and osteogenesis during bone regeneration, the aim of this study was to investigate if their sequential release could enhance BMP-2-induced bone formation. A composite consisting of poly(lactic-co-glycolic acid) microspheres loaded with BMP-2 embedded in a poly(propylene) scaffold surrounded by a gelatin hydrogel loaded with VEGF was used for the sequential release of the growth factors. Empty composites or composites loaded with VEGF and/or BMP-2 were implanted ectopically and orthotopically in Sprague-Dawley rats (n=9). Following implantation, the local release profiles were determined by measuring the activity of (125)I-labeled growth factors using scintillation probes. After 8 weeks blood vessel and bone formation were analyzed using microangiography, microCT and histology. The scaffolds exhibited a large initial burst release of VEGF within the first 3 days and a sustained release of BMP-2 over the full 56-day implantation period. Although VEGF did not induce bone formation, it did increase the formation of the supportive vascular network (p=0.03) in ectopic implants. In combination with local sustained BMP-2 release, VEGF significantly enhanced ectopic bone formation compared to BMP-2 alone (p=0.008). In the orthotopic defects, no effect of VEGF on vascularisation was found, nor was bone formation higher by the combination of growth factors, compared to BMP-2 alone. This study demonstrates that a sequential angiogenic and osteogenic growth factor release may be beneficial for the enhancement of bone regeneration.

Non-invasive monitoring of BMP-2 retention and bone formation in composites for bone tissue engineering using SPECT/CT and scintillation probes.

Non-invasive imaging can provide essential information for the optimization of new drug delivery-based bone regeneration strategies to repair damaged or impaired bone tissue. This study investigates the applicability of nuclear medicine and radiological techniques to monitor growth factor retention profiles and subsequent effects on bone formation. Recombinant human bone morphogenetic protein-2 (BMP-2, 6.5 microg/scaffold) was incorporated into a sustained release vehicle consisting of poly(lactic-co-glycolic acid) microspheres embedded in a poly(propylene fumarate) scaffold surrounded by a gelatin hydrogel and implanted subcutaneously and in 5-mm segmental femoral defects in 9 rats for a period of 56 days. To determine the pharmacokinetic profile, BMP-2 was radiolabeled with (125)I and the local retention of (125)I-BMP-2 was measured by single photon emission computed tomography (SPECT), scintillation probes and ex vivo scintillation analysis. Bone formation was monitored by micro-computed tomography (microCT). The scaffolds released BMP-2 in a sustained fashion over the 56-day implantation period. A good correlation between the SPECT and scintillation probe measurements was found and there were no significant differences between the non-invasive and ex-vivo counting method after 8 weeks of follow up. SPECT analysis of the total body and thyroid counts showed a limited accumulation of (125)I within the body. Ectopic bone formation was induced in the scaffolds and the femur defects healed completely. In vivo microCT imaging detected the first signs of bone formation at days 14 and 28 for the orthotopic and ectopic implants, respectively, and provided a detailed profile of the bone formation rate. Overall, this study clearly demonstrates the benefit of applying non-invasive techniques in drug delivery-based bone regeneration strategies by providing detailed and reliable profiles of the growth factor retention and bone formation at different implantation sites in a limited number of animals.

Local antibiotic delivery with OsteoSet, DBX, and Collagraft.

Biodegradable local antibiotic delivery systems have gained interest for prophylaxis and treatment of musculoskeletal infections. We studied the biodegradable materials Osteo- Set®, DBX® and Collagraft® for local delivery of vancomycin and gentamicin in vitro. We determined the antimicrobial activity of vancomycin and gentamicin after mixing with each biodegradable material and determined the release of each antimicrobial from each material in an intermittent flow chamber. Antimicrobial activity was expressed as percent of antimicrobial loaded into each sample that was detected; antimicrobial release was expressed as concentration (μg/mL) after timed intervals of chamber flow, peak concentration, area under the curve and percent antimicrobial recovered. Activity of vancomycin after mixing with Osteo- Set®, DBX® and Collagraft® was > 73%. Activity of gentamicin after mixing with DBX® was 100%; after mixing with OsteoSet® and Collagraft® it was reduced to < 61%. AUC0-48hrs of vancomycin was 469, 426 and 432 μg × hr/mL, and the AUC0-48hrs of gentamicin was 368, 306 and 301 μg × hr/mL after release from OsteoSet®, DBX®, and Collagraft®, respectively. Recovered percentages of vancomycin were 39%, 11% and 25%, and recovered percentages of gentamicin were 39%, 9% and 23% after release from OsteoSet®, DBX®, and Collagraft®, respectively. OsteoSet®, DBX® and Collagraft® may be suitable for local delivery of vancomycin and gentamicin.

Delayed treatment of elbow pain and dysfunction following Essex-Lopresti injury with metallic radial head replacement: A case series

BACKGROUND Chronic longitudinal radioulnar dissociation has been associated with unpredictable and generally unfavorable outcomes. Metallic radial head replacement may address this treatment deficiency. METHODS Eight patients were treated with a metallic radial head replacement for chronic longitudinal radioulnar dissociation. The average treatment delay was 3.3 years. All eight patients were seen for a clinical and radiographic assessment. RESULTS Five of the 8 failed after a mean of 3 years (range, 1-5.7). Revision to bipolar metallic radial head replacement was successful in the short term in 2 of 3 that failed from aseptic loosening. One of 2 failures due to painful radiocapitellar arthritis was salvaged with a capitellar replacement. DISCUSSION Reconstruction for symptoms following an Essex-Lopresti injury remains problematic. A metallic radial head implant appears to be an effective adjunct, but not a perfect solution in all patients. Recognition of the negative impact of residual lateral ulnar collateral ligament laxity is an important observation and should be specifically addressed with the reconstructive procedure. CONCLUSION Metallic monoblock radial head replacement did not reliably address the functional deficiency from chronic radioulnar dissociation primarily due to malalignment and implant loosening. A cemented bipolar radial head implant may provide a better alternative as a long-term solution. Regardless, ligamentous integrity at the elbow should also be addressed at the time of the reconstruction.

Radial Head Arthroplasty: A Systematic Review.

Background:Despite the expanding body of literature on radial head arthroplasty, the increasing understanding of elbow anatomy, biomechanics, and kinetics, and the evolution of surgical techniques and prosthesis designs, there is currently no evidence to support one type of radial head prosthesis over another. The purposes of the present report were to review the literature and to explore the association between prosthesis design variables and the timing of surgery and the outcome of modern radial head arthroplasty. Methods:The literature search was limited to studies involving skeletally mature patients. Major databases were searched from January 1940 to May 2015 to identify studies relating to functional and subjective outcomes and radiographic results after radial head arthroplasty. Results:Thirty articles involving 727 patients were included. Seventy percent of the implants were made of cobalt-chromium, 15% were made of pyrocarbon, 9% were made of titanium, and 6% were made of Vitallium. Seventy percent were monopolar, and 30% were bipolar. Twenty-one percent were cemented in place, 32% were press-fit, 32% were intentionally loose-fit, and 15% were fixed with an expandable stem. The weighted average duration of follow-up was 45 months. The rate of revision ranged from 0% to 29% among studies. The incidence of revision was 8% during 2,714 person-years of follow-up across all 727 patients, yielding a crude overall revision rate of 2.06 per 100 person-years of follow-up. The revision rate was not significantly affected by prosthesis polarity, material, or fixation technique, nor was it significantly affected by the delay of treatment. There was also no significant effect of prosthesis polarity, material, or fixation technique on postoperative range of motion. The Mayo Elbow Performance Score was only reported for half of the overall patient population, but, among those patients, the combined rate of excellent and good results was 85%. Seven percent of the overall patient population underwent secondary surgery about the elbow other than revision surgery. Twenty-three percent were reported to have 1 or more complications. Conclusions:On the basis of our analysis of the peer-reviewed English-language literature on radial head arthroplasty from January 1940 to May 2015, there seems to be no evidence to support one type of radial head prosthesis over another. The only exception is that silicone prostheses have been shown to be biologically and biomechanically insufficient. Level of Evidence:Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Prosthesis design and stress profile after hip resurfacing: a finite element analysis

Purpose. To evaluate the effect of prosthesis design on stress profile in the proximal femur after hip resurfacing. Methods. The von Mises stress profile of the native femur was simulated and compared with that of resurfaced femurs using various prosthetic materials (titanium, cobalt-chrome, ceramic), stem lengths (normal, half, short, and no stem), and femoral head coverage (shell size) [260°, 220°, 180°, and 140°]. Results. Hip resurfacing altered the stress profile of the cancellous (but not cortical) bone of the femoral neck. Maximal cortical stresses were observed at the posterior half of the medial femoral neck. The stress profile of the native femur was most similar to that of the resurfaced femur made of titanium, with a short or no stem and 260 degrees of femoral head coverage (shell size). Conclusion. Optimising prosthesis design by minimising biomechanical alterations seems a valid approach to achieving favourable long-term outcomes. Cadaveric and in vivo studies are needed to confirm the clinical relevance and feasibility.

Press-fit bipolar radial head arthroplasty, midterm results

BACKGROUND Theoretical advantages of bipolar compared with monopolar radial head arthroplasty include better accommodation of radiocapitellar malalignment, reduction of capitellar abrasion, and reduction of stress at the bone-implant interfaces. Our purpose was to report the midterm results of press-fit bipolar radial head arthroplasty. METHODS Thirty patients were treated by press-fit bipolar radial head arthroplasty for acute fracture of the radial head, failed earlier treatment, or post-traumatic sequelae. Three patients were lost to follow-up. Results are presented for the remaining 27 patients. RESULTS At mean follow-up of 48 months (range, 28-73), there had been 3 (11%) revisions. Two involved conversion to prosthetic radiocapitellar hemiarthroplasty for symptomatic capitellar abrasion; a third involved exchange of the articular component (ie, head) for instability. In all, the stems appeared well fixed. A prosthesis in a subluxed position accounted for the 1 (4%) additional radiologic failure. The average flexion-extension arc was 136° (range, 120°-145°), and the average pronation-supination arc was 138° (range, 70°-180°). According to the Mayo Elbow Performance Score, the combined excellent and good results accounted for 70%. CONCLUSIONS The overall midterm outcome of this series of 30 press-fit bipolar radial head arthroplasties can be considered favorable. Although the revision rate was 11%, the stems were well fixed in all. There was 1 (4%) additional radiologic failure. We suggest considering a press-fit bipolar radial head prosthesis for acute comminuted radial head fractures with limited bone loss of the proximal radius.

Cemented bipolar radial head arthroplasty: midterm follow-up results

BACKGROUND Theoretical advantages of bipolar over monopolar radial head arthroplasty include better accommodation of radiocapitellar malalignment, reduction of capitellar abrasion, and reduction of stress at the bone-to-cement and cement-to-implant interfaces. Our purpose was to report the midterm results of cemented bipolar radial head arthroplasty. METHODS Twenty-five patients were treated by cemented bipolar radial head arthroplasty for acute fracture of the radial head, earlier treatment that had failed, or posttraumatic sequelae. One patient refused follow-up after surgery. Results are presented for the remaining 24 patients. RESULTS At a mean follow-up of 50 months (range, 24-72 months), 1 prosthesis (4%) had been removed 2 years after implantation for dissociation of the prosthesis due to failure of the snap-on mechanism. There were 2 (8%) additional radiologic failures in the subluxated position: 1 prosthesis due to malalignment of the radius onto the capitellum and another due to ulnohumeral erosion. The average flexion-extension arc was 129° (range, 80°-140°), and the average pronation-supination arc was 131° (range, 40°-180°). According to the Mayo Elbow Performance Score, the combined excellent and good results accounted for 83%. In 8 patients, the bipolar design compensated for radiocapitellar malalignment. CONCLUSIONS The overall midterm outcome of this series of 25 cemented bipolar radial head arthroplasties can be considered favorable. There was 1 (4%) revision and 2 (8%) additional radiologic failures. The bipolar design was able to compensate for radiocapitellar malalignment. We suggest considering a cemented bipolar radial head prosthesis in case of concerns about radiocapitellar alignment.

Radiocapitellar prosthetic arthroplasty: short-term to midterm results of 19 elbows

BACKGROUND Few studies have discussed the short-term results of radiocapitellar (RC) prosthetic arthroplasty (PA). In this study, we assessed the short-term to midterm functional and radiographic results of elbows after RC PA. Our secondary aim was to assess the survival of the RC PA. METHODS We included 19 elbows in 18 patients with a mean follow-up of 35 months (range, 12-88 months). Patients were examined for instability and range of motion and were assessed using Mayo Elbow Performance Index and Oxford Elbow Score at any subsequent visits. RC PA was the primary treatment in 16 elbows, and 3 were revision radial head arthroplasty with concomitant capitellar resurfacing. RESULTS Range of motion, pain, and functional scores improved significantly from the preoperative to the final follow-up visit. Categoric grouping of the final Mayo Elbow Performance Index outcome scores showed 9 excellent, 5 good, 3 fair, 0 poor, and 2 missing data. However, stability of the elbow remained unchanged. There was no pain in 11 patients, mild pain in 5, and moderate pain in 3. Radiographic assessment showed no significant progress in ulnohumeral arthritis, although 3 elbows showed osteoarthritis progression to a higher grade. There were no major complications, including infection, revision, disassembly of the components, or conversion to total elbow arthroplasty. Survival of the RC PA was 100%. CONCLUSION Elbow arthritis seems to become stationary after RC PA. Symptomatic RC osteoarthritis would probably benefit from RC PA regardless of the etiology.