Deformable titanium for acetabular revision surgery: a proof of concept.

Custom-made triflange acetabular implants are increasingly used in complex revision surgery where supporting bone stock is diminished. In most cases these triflange cups induce stress-shielding. A new concept for the triflange is introduced that uses deformable porous titanium to redirect forces from the acetabular rim to the bone stock behind the implant and thereby reduces further stress-shielding. This concept is tested for deformability and primary stability.Three different designs of highly porous titanium cylinders were tested under compression to determine their mechanical properties. The most promising design was used to design five acetabular implants either by incorporating a deformable layer at the back of the implant or by adding a separate generic deformable mesh behind the implant. All implants were inserted into sawbones with acetabular defects followed by a cyclic compression test of 1800N for 1000 cycles.The design with a cell size of 4 mm and 0.2 mm strut thickness performed the best and was applied for the design of the acetabular implants. An immediate primary fixation was realized in all three implants with an incorporated deformable layer. One of the two implants with a separate deformable mesh needed fixation with screws. Cyclic tests revealed an average additional implant subsidence of 0.25 mm that occurred in the first 1000 cycles with minimal further subsidence thereafter.It is possible to realize primary implant fixation and stability in simulated large acetabular revision surgery using a deformable titanium layer behind the cup. Additional research is needed for further implementation of such implants in the clinic.

Toward Antibacterial Coatings for Personalized Implants.

The complex reconstructive surgeries for which patient-specific orthopedic, maxillofacial, or dental implants are used often necessitate wounds that are open for a considerable amount of time. Unsurprisingly, this allows bacteria to establish implant-associated infection, despite the scrupulous sterilization efforts made during surgery. Here, we developed a prophylactic bactericidal coating via electrophoretic deposition technology for two 3D-printed porous titanium implant designs. The surface characteristics, antibiotic release behavior, antibacterial properties, and impact on osteoblast cell proliferation of the optimized coatings were investigated. The results unequivocally confirmed the biofunctionality of the implants in vitro. This study reveals a new avenue for future antibacterial patient-specific implants.

Treating infections with ionizing radiation: a historical perspective and emerging techniques.

BACKGROUND: Widespread use and misuse of antibiotics have led to a dramatic increase in the emergence of antibiotic resistant bacteria, while the discovery and development of new antibiotics is declining. This has made certain implant-associated infections such as periprosthetic joint infections, where a biofilm is formed, very difficult to treat. Alternative treatment modalities are needed to treat these types of infections in the future. One candidate that has been used extensively in the past, is the use of ionizing radiation. This review aims to provide a historical overview and future perspective of radiation therapy in infectious diseases with a focus on orthopedic infections. METHODS: A systematic search strategy was designed to select studies that used radiation as treatment for bacterial or fungal infections. A total of 216 potentially relevant full-text publications were independently reviewed, of which 182 focused on external radiation and 34 on internal radiation. Due to the large number of studies, several topics were chosen. The main advantages, disadvantages, limitations, and implications of radiation treatment for infections were discussed. RESULTS: In the pre-antibiotic era, high mortality rates were seen in different infections such as pneumonia, gas gangrene and otitis media. In some cases, external radiation therapy decreased the mortality significantly but long-term follow-up of the patients was often not performed so long term radiation effects, as well as potential increased risk of malignancies could not be investigated. Internal radiation using alpha and beta emitting radionuclides show great promise in treating fungal and bacterial infections when combined with selective targeting through antibodies, thus minimizing possible collateral damage to healthy tissue. CONCLUSION: The novel prospects of radiation treatment strategies against planktonic and biofilm-related microbial infections seem feasible and are worth investigating further. However, potential risks involving radiation treatment must be considered in each individual patient.

A multifunctional silk coating on additively manufactured porous titanium to prevent implant-associated infection and stimulate bone regeneration.

Despite tremendous progress in the design and manufacturing of metallic implants, they do not outlive the patient. To illustrate, more than half of hip replacements will fail, mainly due to implant infection and loosening. Surface engineering approaches and, in particular, coatings can facilitate implant bio-functionality via the recruitment of more host cells for new bone formation and inhibition of bacterial colonization. Here, we used electrophoretic deposition to apply a silk fibroin solution consisting of tricalcium phosphate (TCP) and vancomycin as a coating on the surface of additively-manufactured porous titanium. Furthermore, the surface properties of the coatings developed and the release kinetics of the vancomycin were studied to evaluate the applied coating. The in vitro antibacterial behavior of the multifunctional coating, as well as the cell viability and osteogenic differentiation of the MC3T3-E1 cell line were extensively studied. The biomaterials developed exhibited an antibacterial behavior with a reduction of up to four orders of magnitude in both planktonic and adherent bacteria for 6 h and 1 d. A live-dead assay, the Alamar Blue activity, the DNA content, and cytoskeleton staining demonstrated a significant increase in the cell density of the coated groups versus the as-manufactured ones. The significantly enhanced calcium deposition and the increase in mineralization for the groups with TCP after 21 and 28 d, respectively, demonstrate upregulation of the MC3T3 cells' osteogenic differentiation. Our results collectively show that the multifunctional coating studied here can be potentially used to develop a new generation of orthopedic implants.

Bactericidal coating to prevent early and delayed implant-related infections.

The occurrence of an implant-associated infection (IAI) with the formation of a persisting bacterial biofilm remains a major risk following orthopedic biomaterial implantation. Yet, progress in the fabrication of tunable and durable implant coatings with sufficient bactericidal activity to prevent IAI has been limited. Here, an electrospun composite coating was optimized for the combinatorial and sustained delivery of antibiotics. Antibiotics-laden poly(ε-caprolactone) (PCL) and poly`1q`(lactic-co glycolic acid) (PLGA) nanofibers were electrospun onto lattice structured titanium (Ti) implants. In order to achieve tunable and independent delivery of vancomycin (Van) and rifampicin (Rif), we investigated the influence of the specific drug-polymer interaction and the nanofiber coating composition on the drug release profile and durability of the polymer-Ti interface. We found that a bi-layered nanofiber structure, produced by electrospinning of an inner layer of [PCL/Van] and an outer layer of [PLGA/Rif], yielded the optimal combinatorial drug release profile. This resulted in markedly enhanced bactericidal activity against planktonic and adherent Staphylococcus aureus for 6 weeks as compared to single drug delivery. Moreover, after 6 weeks, synergistic bacterial killing was observed as a result of sustained Van and Rif release. The application of a nanofiber-filled lattice structure successfully prevented the delamination of the multi-layer coating after press-fit cadaveric bone implantation. This new lattice design, in conjunction with the multi-layer nanofiber structure, can be applied to develop tunable and durable coatings for various metallic implantable devices. This is particularly appealing to tune the release of multiple antimicrobial agents over a period of weeks to prevent early and delayed onset IAI.

Radioimmunotherapy of methicillin-resistant Staphylococcus aureus in planktonic state and biofilms.

BACKGROUND: Implant associated infections such as periprosthetic joint infections are difficult to treat as the bacteria form a biofilm on the prosthetic material. This biofilm complicates surgical and antibiotic treatment. With rising antibiotic resistance, alternative treatment options are needed to treat these infections in the future. The aim of this article is to provide proof-of-principle data required for further development of radioimmunotherapy for non-invasive treatment of implant associated infections. METHODS: Planktonic cells and biofilms of Methicillin-resistant staphylococcus aureus are grown and treated with radioimmunotherapy. The monoclonal antibodies used, target wall teichoic acids that are cell and biofilm specific. Three different radionuclides in different doses were used. Viability and metabolic activity of the bacterial cells and biofilms were measured by CFU dilution and XTT reduction. RESULTS: Alpha-RIT with Bismuth-213 showed significant and dose dependent killing in both planktonic MRSA and biofilm. When planktonic bacteria were treated with 370 kBq of 213Bi-RIT 99% of the bacteria were killed. Complete killing of the bacteria in the biofilm was seen at 185 kBq. Beta-RIT with Lutetium-177 and Actinium-225 showed little to no significant killing. CONCLUSION: Our results demonstrate the ability of specific antibodies loaded with an alpha-emitter Bismuth-213 to selectively kill staphylococcus aureus cells in vitro in both planktonic and biofilm state. RIT could therefore be a potentially alternative treatment modality against planktonic and biofilm-related microbial infections.

Data on a rat infection model to assess porous titanium implant coatings.

A model is needed to study the effectiveness of different anti-bacterial coatings on complex metal implants in a bone environment. This article shares data on the design of porous titanium implants for intramedullary implantation in the proximal rat tibia. The implant length, diameter and porosity were optimized after testing on cadaveric specimens. This article shares data on which parameters are critical to establish a chronic implant infection in Sprague Dawley rats when using the new implant design. To this end, different strains of Staphylococcus aureus and inoculation doses were investigated.

Antibacterial and immunogenic behavior of silver coatings on additively manufactured porous titanium.

Implant-associated infections (IAI) are often recurrent, expensive to treat, and associated with high rates of morbidity, if not mortality. We biofunctionalized the surface of additively manufactured volume-porous titanium implants using electrophoretic deposition (EPD) as a way to eliminate the peri-operative bacterial load and prevent IAI. Chitosan-based (Ch) coatings were incorporated with different concentrations of silver (Ag) nanoparticles or vancomycin. A full-scale in vitro and in vivo study was then performed to evaluate the antibacterial, immunogenic, and osteogenic activity of the developed implants. In vitro, Ch + vancomycin or Ch + Ag coatings completely eliminated, or reduced the number of planktonic and adherent Staphylococcus aureus by up to 4 orders of magnitude, respectively. In an in vivo tibia intramedullary implant model, Ch + Ag coatings caused no adverse immune or bone response under aseptic conditions. Following Staphylococcus aureus inoculation, Ch + vancomycin coatings reduced the implant infection rate as compared to chitosan-only coatings. Ch + Ag implants did not demonstrate antibacterial effects in vivo and even aggravated infection-mediated bone remodeling including increased osteoclast formation and inflammation-induced new bone formation. As an explanation for the poor antibacterial activity of Ch + Ag implants, it was found that antibacterial Ag concentrations were cytotoxic for neutrophils, and that non-toxic Ag concentrations diminished their phagocytic activity. This study shows the potential of EPD coating to biofunctionalize porous titanium implants with different antibacterial agents. Using this method, Ag-based coatings seem inferior to antibiotic coatings, as their adverse effects on the normal immune response could cancel the direct antibacterial effects of Ag nanoparticles. STATEMENT OF SIGNIFICANCE: Implant-associated infections (IAI) are a clinical, societal, and economical burden. Surface biofunctionalization approaches can render complex metal implants with strong local antibacterial action. The antibacterial effects of inorganic materials such as silver nanoparticles (Ag NPs) are often highlighted under very confined conditions in vitro. As a novelty, this study also reports the antibacterial, immunogenic, and osteogenic activity of Ag NP-coated additively-manufactured titanium in vivo. Importantly, it was found that the developed coatings could impair the normal function of neutrophils, the most important phagocytic cells protecting us from IAI. Not surprisingly, the Ag NP-based coatings were outperformed by an antibiotic-based coating. This emphasizes the importance of also targeting implant immune-modulatory functions in future coating strategies against IAI.

Pseudotumor in metal-on-metal hip arthroplasty: a comparison study of three grading systems with MRI.

OBJECTIVE: Pseudotumors, a well-known complication of metal-on-metal total hip arthroplasty (MoM THA), are well identified on metal artifact-reducing sequences magnetic resonance imaging (MARS-MRI). Several MRI grading systems are described in the orthopedic literature, but their validity is unknown in large clinical studies. Our study was undertaken to describe the classification of pseudotumors in a preselected cohort divided into high- and low-risk patients, using three pseudotumor grading systems applied on MARS-MRI, and to determine the interobserver reliability of the grading systems. PATIENTS AND METHODS: A retrospective study was performed on 377 consecutive patients (240 MRI scans) treated with an M2a-38 and Taperloc stem combination (Biomet, Warsaw, IN, USA). Patients were divided into a high-risk and a low-risk group based on previous published risk factors. Two observers determined the presence of pseudotumors using three different pseudotumor grading systems for classifying MARS-MRI results. RESULTS: The prevalence of pseudotumors as determined with MARS-MRI was 59% in our high-risk group, 0% in the low-risk group and 43% in the control group. Serum cobalt values were increased in the high-risk group. The kappa values of the Anderson, Hauptfleisch and Matthies grading system scores were 0.43, 0.44, and 0.49 respectively. CONCLUSIONS: High-risk patients are at a high risk for pseudotumor development. No pseudotumor development was found in low-risk patients. Interobserver reliability scored best with the Matthies system, but all three grading systems showed only a moderate agreement.

Femoral fit in ABG-II hip stems, influence on clinical outcome and bone remodeling: a radiographic study.

INTRODUCTION: In a consecutive series of 64 patients with an ABG-II stem, we analyzed whether the tightness of the fit of the prosthesis affected bone remodeling and if there was a relation between clinical and radiological results. MATERIALS AND METHODS: Radiographic analysis of bone remodeling in different Gruen zones was done. Bone density changes were graded as present or absent in the AP and lateral radiographs as compared with the previous sets of radiographs. Bone remodeling was compared to literature values of the ABG-I stem. Three stem levels were defined. The proximal level was set at the upper border of the lesser trochanter, the mid-stem level at halfway the stem and the distal level 1 cm above the tip of the prosthesis. Femoral fit was defined as tight when the ratio of the fit was >/=0.8 and as non-tight if the fit was <0.8. The incidence of thigh pain was scored using the Merle d'Aubigne (MdA) hip score. RESULTS: Proximal bone resorption in Gruen zone 1 was 26.6% and in zone 7, 34.4% compared to 48 and 45% for the ABG-I stem after 5 years. No correlation was found between femoral fit and radiological changes. Proximal and distal fit was significantly lower for patients with thigh pain than without thigh pain. Patients with a non-tight proximal fit produced significantly more varus (17/30 = 56.7%) than patients with a tight proximal fit (2/34 = 5.9%; P < 0.01). CONCLUSION: Femoral fit in ABG-II does not predict certain radiological changes, but less proximal bone resorption confirms the design changes from ABG-I to ABG-II. A non-tight proximal fit is correlated with varus position of the stem. Thigh pain is correlated with a poor fit and fill of the femoral stem.

The influence of implant design on periprosthetic bone remodelling of two types of uncemented HA-coated hip stems. A two-year follow-up study using DEXA.

UNLABELLED: Proximal bone resorption and an increased fracture rate in the ABG-I stem has been shown. For these reasons the ABG-I stem design was changed to the ABG-II. In this study periprosthetic bone loss around the ABG-I vs ABG-II is compared to verify if the design changes resulted in improved proximal bone preservation. METHODS: 51 patients were randomised to either the ABG-I or ABG-II hip prosthesis. Periprosthetic BMD change at various time points was measured using DEXA. Between the two groups (age, gender, weight etc.) no statistical difference was encountered. Compared to the baseline at two years the ABG-II preserved bone better proximally (e.g. zone 7: ABG-II: -3.7%, ABG-I: -11.9%, p=0.05) than the ABG-I. Distally, the trend was opposite and less bone loss was measured for the ABG-I than the ABG-II in zones 3, 4 and 5 (n.s.). CONCLUSION: this study confirms the philosophy behind the design changes from the ABG-I to ABG-II stem where increased elasticity, more proximal HA-coating, a shorter and distally polished stem, were meant to reduce proximal bone resorption. In future this may lead to fewer periprosthetic fractures and to less complicated revision surgery.

Periprosthetic fractures around cementless hydroxyapatite-coated femoral stems.

We studied 14 periprosthetic femoral fractures out of a series of 619 hydroxyapatite coated hip implants and compared the outcome to published treatment algorithms using the Vancouver classification. There were five type A fractures, six B1, two B2, and one type B3 fracture. All but one type A fractures were treated conservatively. Compared with the Vancouver classification, we observed a different fracture type in the type B fractures. No fractures at the tip of the stem were seen, as in cemented implants. Three B1 fractures were treated operatively due to fracture displacement, and three were treated conservatively. The B2 and B3 fractures were managed with long, uncemented, revision stems because of a disrupted bone-prosthesis interface. All fractures healed well. This study confirms that the modified algorithm of management of periprosthetic fractures, using the Vancouver classification, is a simple, reproducible, classification system for uncemented prostheses. Conservative treatment is a valid option if the implant is stable whilst surgical intervention is mandatory if the implant is loose.

Transcatheter arterial chemoembolization of liver tumors: effects of embolization protocol on injectable volume of chemotherapy and subsequent arterial patency.

The purpose of this study was to determine whether transcatheter arterial chemoembolization (TACE) protocol affects the total volume of chemotherapy injected into the liver as well as subsequent arterial patency. A total of 160 patients with primary or secondary liver cancer were treated with 3 different chemoembolization protocols at a single institution. Data were analyzed retrospectively. Group 1 (n = 36) consisted of slurry of chemotherapy, oil and polyvinyl alcohol particles (PVA), group 2 (n = 91), chemotherapy and oil followed by PVA, and group 3 (n = 33), chemotherapy and oil followed by Gelfoam pledgets. The total volume of chemotherapy injected into the liver was recorded. Arterial patency was determined during subsequent chemoembolizations. The mean percentage of total intended chemotherapy dose administered was 54.6% for group 1, 75.3% for group 2, and 80.6% for group 3. Arterial patency at follow-up angiography was 56% for group 1, 74% for group 2, and 81% for group 3. The slurry protocol (group 1) significantly reduced arterial patency and injectable volume of chemotherapy during TACE.

Axillary lymph node ratio and total number of removed lymph nodes: predictors of survival in stage I and II breast cancer.

AIMS: Presence of axillary lymph node metastases is considered the most important prognostic factor for breast cancer survival. In a period of increasing popularity for the sentinel node procedure, clarity about the possible relation between axillary dissection and survival is essential. This study investigated whether the total number of removed lymph nodes and the ratio of invaded/removed lymph nodes (lymph node ratio (LNR) would prove to be independent prognostic factors for survival. METHODS: Data from 453 consecutive patients with stage I or II breast cancer were studied retrospectively. The total number of removed lymph nodes and the LNR were analysed for their prognostic value in comparison with known prognostic factors. RESULTS: Node-negative patients with < 14 lymph nodes removed had a 10 year survival of 79% compared with 89% in patients with > or = 14 lymph nodes removed (P=0.005). The 10 year survival for patients with an LNR > or = 0.2 was 52%, compared with 73% for patients with an LNR < 0.2 (P<0.0001). A Cox proportional hazards model showed that, for node-negative patients, only age and total number of removed lymph nodes were significant prognostic factors. For node-positive patients, age, total number of removed lymph nodes and the LNR were significant risk factors for survival outcome. The LNR was also significantly associated with the presence of distant metastases during follow-up (hazard ratio 3.56, range 1.63-7.77). CONCLUSIONS: In stage I and II breast cancer, a favourable prognosis was found for node-negative patients with > or = 14 removed lymph nodes. Before axillary lymph node dissection with its well-defined survival prognosis is replaced by less invasive staging methods, long-term survival using new staging techniques needs to be defined. For node-positive patients, the LNR proved to be an excellent predictor for survival outcome or development of metastatic disease. Selection of lymph node-positive patients based on the LNR may guide specific adjuvant treatment choices.

Results of salvage abdominoperineal resection for recurrent anal carcinoma following combined chemoradiation therapy.

Combined chemotherapy and radiation therapy is the standard treatment for epidermoid carcinoma of the anal canal. Failures are often not associated with distant recurrence and are therefore potentially amenable to salvage abdominoperineal resection. The aim of this study was to review our experience with abdominoperineal resection following failure of chemoradiation therapy for epidermoid carcinoma of the anus. Between 1980 and 1998, 17 patients underwent salvage abdominoperineal resection following failure of chemoradiation therapy. Four patients were excluded from survival analysis because resection was performed with palliative intent. Survival curves were based on the method of Kaplan and Meier, and univariate analysis of predictive variables was performed using the log-rank test. Twelve patients underwent abdominoperineal resection for persistent disease and five patients for recurrent disease. No operative deaths occurred, but local complications including perineal wound infection and wound breakdown was seen in 8 of 17 patients and 6 of 17 patients, respectively. Patients undergoing omental flap reconstruction (n = 3) or no pelvic reconstruction (n = 5) had a higher incidence of perineal breakdown compared to those undergoing muscle flap reconstruction (n = 9) (P <0.05). The median follow-up time for the patients operated on with curative intent was 53 months. The 5-year actuarial survival was 47%. Potential prognostic factors that were not found to have an impact on survival included margin status of resection, sphincter invasion, and degree of differentiation. Only pathologic tumor size greater than 5.0 cm (P <0.001) and age over 55 years (P <0.05) adversely affected survival. Selected patients with recurrent or persistent anal carcinoma following chemoradiation therapy can be offered salvage abdominoperineal resection. This operation is associated with a high incidence of local wound complications, and muscle flap reconstruction should be considered when possible. Prolonged survival can be achieved in some patients following salvage resection for epidermoid carcinoma of the anal canal.

Adult hyperinsulinemic hypoglycemia not caused by an insulinoma: a report of two cases.

Nesidioblastosis is rare in adults and accounts for 0.5-5% of cases of organic hyperinsulinemia. The diagnosis of nesidioblastosis should be considered when peroperative imaging modalities fail to localize a lesion in patients with hyperinsulinism. Two female patients, aged 55 and 16 years, with hyperinsulinemic hypoglycemia are reported. Somatostatin receptor scintigraphy showed slight focal activity in both patients. The first patient underwent a Whipple procedure and became diabetic. The second patient underwent a distal hemi-pancreatectomy and suffered from recurrent hypoglycemic episodes 3 months after surgery, for which she is presently being treated with octreotide. Histological examination of the resected pancreata revealed focally increased islet tissue and a number of slightly hypertrophic beta cells. Such histological abnormalities have been related to functional changes of beta-cells. In infantile nesidioblastosis, a proportion of cases has been associated with mutations in one of several genes. Whether such mutations, leading to hyperinsulinism, also play a role in adult nesidioblastosis is presently unknown.

Paracrine interactions between mesothelial and colon-carcinoma cells in a rat model.

This study used a co-culture system with Transwell tissue-culture inserts to investigate the role of primary cultures of rat peritoneal mesothelial cells on the proliferation of rat colon-carcinoma cells (CC531 cells). Mesothelial cells significantly inhibited the growth of CC531 cells, while, conversely, CC531 cells stimulated the growth of mesothelial cells. Receptor-binding studies demonstrated the presence of high-affinity IGF-I receptors on the mesothelial and CC531 cells. Both cell types also produced IGF-I, as measured by radioimmunoassay. IGF-I stimulated DNA synthesis in mesothelial cells, but had no effect on the growth of CC531 cells. In co-culture, it was found that IGF-I potentiated the inhibitory effect of mesothelial cells on CC531 cells. The effect of IGF-I on mesothelial-cell proliferation was additive to the stimulatory effect of CC531 cells. TGF-beta had no effect on the growth of the CC531 cells, suggesting that this growth (-inhibitory) factor is not involved in the inhibitory effect of mesothelial cells on CC531 cell growth. The study provides evidence for the existence of a paracrine loop between mesothelial and colon-carcinoma cells, giving more insight into the basic cellular mechanisms that may modulate the growth of intraperitoneal colon carcinoma. Inhibition of CC531-cell proliferation by rat mesothelial cells might explain the earlier finding that tumour cells grow poorly in a surgically uncompromised abdomen.

Changes in the renin-angiotensin-aldosterone system and in sodium and potassium balance during development of renal hypertension in rats.

1. The relationships between the renin-angiotensin-aldosterone system, sodium and potassium balance and systolic blood pressure were studied during development of moderate (160-180 mmHg; clip i.d. 0.25 mm) and severe (200-230 mmHg; clip i.d. 0.20 mm) renal hypertension in rats with an undisturbed contralateral kidney. 2. In severely hypertensive rats renin activity in the peripheral plasma increased from day 9, by which time the systolic blood pressure was elevated to 160-180 mmHg. The rate of total corticosteroid and aldosterone production in vitro increased from day 14 and plasma renin substrate concentration increased from day 24. In moderately hypertensive rats, none of these changes occurred. 3. During the first 10 days after the application of 0.25 and 0.20 mm clips, sodium and potassium retention/g gain in body weight were higher than in sham-operated controls. During the next 10 days, the positive balance stabilized in animals with a 0.25 mm clip whereas, in animals with a 0.20 mm clip, sodium and potassium balance returned to the level of the sham-operated controls through increased renal losses. Despite these changes the systolic pressure rose further in animals with a 0.20 mm clip. 4. The initial sodium retention could be a factor in the early rise of blood pressure and could account for the delay in the rise of peripheral plasma renin activity. The subsequent loss of the retained sodium and potassium during the development of severe hypertension could have facilitated the rise in peripheral plasma renin activity, but did not initiate this rise.