Background: the primary challenge with implant infections is the formation of biofilm, which harbors dormant bacteria that reduce the effectiveness of antibiotics and amplify antibiotic resistance, exacerbating the global antimicrobial resistance crisis. A potential novel treatment strategy is radioimmunotherapy, which uses antibodies linked to radioisotopes to deliver targeted radiation to the bacteria and biofilm. We describe the first in vivo use of targeted radiation therapy, employing Actinium-225 (α-radiation) and Lutetium-177 (β-radiation) labeled antibodies to treat a Staphylococcus aureus biofilm-associated intramedullary implant infection. Untargeted radiation in the form of unbound radionuclide treatment was also evaluated. Methods: to assess therapeutic efficacy, bacterial counts were performed on implant and surrounding bone after seven days of follow-up. Biodistribution was evaluated using SPECT/CT and ex vivo gamma counting. Results: radioimmunotherapy using an antibody against wall teichoic acid which was labeled with Actinium-225 and Lutetium-177 achieved bacterial reductions between 45% and 93% on the implant and surrounding bone. Surprisingly, a similar antimicrobial effect was observed with unbound Actinium-225 treatment reducing the bacterial load by 80% on the implant and 98% in the surrounding bone. Indications of maximum tolerated dose (MTD) with Lutetium-177 labeled antibodies were observed through hepatic and renal function evaluations. Conclusions: These results should be interpreted in the context of the study’s constraints, particularly the limited animal sample size. Nonetheless, the results suggest that in vivo applied radiation may help reduce a biofilm-associated infection at the implant site as well as in the surrounding bone. These findings encourage further investigation into the use of targeted and non-targeted radiation, potentially combined with antibiotics, to develop effective strategies for eradicating biofilm-associated implant infections.

Background: Addressing prosthetic joint infections poses a significant challenge within orthopedic surgery, marked by elevated morbidity and mortality rates. The presence of biofilms and infections attributed to Staphylococcus aureus (S. aureus) further complicates the scenario. Objective: To investigate the potential of radioimmunotherapy as an innovative intervention to tackle biofilm-associated infections. Methods: Our methodology involved employing specific monoclonal antibodies 4497-IgG1, designed for targeting wall teichoic acids found on S. aureus and its biofilm. These antibodies were linked with radionuclides actinium-225 (²²⁵Ac) and lutetium-177 (¹⁷⁷Lu) using DOTA as a chelator. Following this, we evaluated the susceptibility of S. aureus and its biofilm to radioimmunotherapy in vitro, assessing bacterial viability and metabolic activity via colony-forming unit enumeration and xylenol tetrazolium assays. Results: Both [²²⁵Ac]4497-IgG1 and [¹⁷⁷Lu]4497-IgG1 exhibited a noteworthy dose-dependent reduction in S. aureus in planktonic cultures and biofilms over a 96-h exposure period, compared to non-specific antibody control groups. Specifically, doses of 7.4 kBq and 7.4 MBq of [²²⁵Ac]4497-IgG1 and [¹⁷⁷Lu]4497-IgG1 resulted in a four-log reduction in planktonic bacterial counts. Within biofilms, 14.8 kBq of [²²⁵Ac]4497-IgG1 and 14.8 Mbq [¹⁷⁷Lu]4497-IgG1 led to reductions of two and four logs, respectively. Conclusion: Our findings underscore the effectiveness of [²²⁵Ac]4497-IgG1 and [¹⁷⁷Lu]4497-IgG1 antibodies in exerting dose-dependent bactericidal effects against planktonic S. aureus and biofilms in vitro. This suggests that radioimmunotherapy might serve as a promising targeted treatment approach for combating S. aureus and its biofilm.

Bacterial infections and antimicrobial resistance are posing substantial difficulties to the worldwide healthcare system. The constraints of conventional diagnostic and therapeutic approaches in dealing with continuously changing infections highlight the necessity for innovative solutions. Aptamers, which are synthetic oligonucleotide ligands with a high degree of specificity and affinity, have demonstrated significant promise in the field of bacterial infection management. This review examines the use of aptamers in the diagnosis and therapy of bacterial infections. The scope of this study includes the utilization of aptasensors and imaging technologies, with a particular focus on their ability to detect conditions at an early stage. Aptamers have shown exceptional effectiveness in suppressing bacterial proliferation and halting the development of biofilms in therapeutic settings. In addition, they possess the capacity to regulate immune responses and serve as carriers in nanomaterial-based techniques, including radiation and photodynamic therapy. We also explore potential solutions to the challenges faced by aptamers, such as nuclease degradation and in vivo instability, to broaden the range of applications for aptamers to combat bacterial infections.

Background and purpose — Hip dysplasia can present challenges for total hip arthroplasty (THA) due to anatomic abnormalities. We aimed to assess the association of age, sex, osteotomies prior to THA, and fixation method on 5-and 10-year revision-free implant survival and patient-reported outcome measures (PROMs) of THAs in patients with hip dysplasia. Methods — Using Dutch Arthroplasty Register data, we studied hip dysplasia patients receiving primary THAs in 2007–2021 (n = 7,465). THAs were categorized by age, pelvic osteotomy prior to THA (yes/no), and fixation (cemented, uncemented, hybrid, reverse hybrid). Kaplan–Meier and multivariable Cox models were used to determine 5-and 10-year revision-free implant survival and adjusted hazard ratios including 95% confidence intervals (CIs). Reasons for revision and PROMs were compared within the categories. Results — We found a 10-year revision-free implant survival of 94.9% (CI 94.3–95.5). Patients younger than 50 years had a 10-year implant survival of 93.3% (CI 91.9– 94.7), Patients with prior pelvic osteotomy had a 10-year implant survival of 92.0% (CI 89.8–94.2). Fixation method and sex were not associated with implant survival. Patients with a prior pelvic osteotomy had more revisions due to cup loosening and reported lower PROM scores than patients without earlier osteotomy. Conclusion — 5-and 10-year revision-free implant survival rates of THA for hip dysplasia are 96.4% and 94.9%. Age and prior osteotomies were associated with decreased implant survival rates in patients with hip dysplasia, while fixation method was not. Prior osteotomies were also associated with reduced PROM scores.

BACKGROUND AND PURPOSE:   The Chiari osteotomy was a regular treatment for developmental hip dysplasia before it became mostly reserved as a salvage therapy. However, the long-term survival of the Chiari osteotomy has not been systematically investigated. We investigated the survival time of the Chiari osteotomy until conversion to total hip arthroplasty (THA) in patients with primary hip dysplasia, and factors which correlated with survival, complications, and the improvement measured in radiographic parameters. PATIENTS AND METHODS: Studies were included when describing patients (> 16 years) with primary hip dysplasia treated with a Chiari osteotomy procedure with 8 years' follow-up. Data on patient characteristics, indications, complications, radiographic parameters, and survival time (endpoint: conversion to THA) were extracted. RESULTS:   8 studies were included. The average postoperative center-edge angle, acetabular head index, and Sharp angle were generally restored within the target range. 3 studies reported Kaplan-Meier survival rates varying from 96% at 10 years to 72% at 20 years' follow-up. Negative survival factors were high age at intervention and pre-existing advanced preoperative osteoarthritis. Moreover, reported complications ranged between 0% and 28.3 %. INTERPRETATION:   The Chiari osteotomy has high reported survival rates and is capable of restoring radiographic hip parameters to healthy values. When carefully selected by young age, and a low osteoarthritis score, patients benefit from the Chiari osteotomy with satisfactory survival rates. The position of the Chiari osteotomy in relation to the periacetabular osteotomies should be further (re-)explored.

A solution for challenging hip dysplasia surgery could be a patient-specific 3D-printed shelf implant that is positioned extra-articular and restores the dysplastic acetabular rim to normal anatomical dimensions. The anatomical correction and biomechanical stability of this concept were tested in a canine model that, like humans, also suffers from hip dysplasia. Using 3D reconstructed computed tomography images the 3D shelf implant was designed to restore the radiological dysplastic hip parameters to healthy parameters. It was tested ex vivo on three dog cadavers (six hips) with hip dysplasia. Each hip was subjected to a biomechanical subluxation test, first without and then with the 3D shelf implant in place. Subsequently, an implant failure test was performed to test the primary implant fixation. At baseline, the dysplastic hips had an average Norberg angle of 88 ± 3° and acetabular coverage of 47 ± 2% and subluxated at an average of 83 ± 2° of femoral adduction. After adding the patient-specific shelf implants the dysplastic hips had an average Norberg angle of 122 ± 2° and acetabular coverage of 67 ± 3% and subluxated at an average of 117 ± 2° of femoral adduction. Implant failure after primary implant fixation occurred at an average of 1330 ± 320 Newton. This showed that the patient-specific shelf implants significantly improved the coverage and stability of dysplastic hips in a canine model with naturally occurring hip dysplasia. The 3D shelf is a promising concept for treating residual hip dysplasia with a straightforward technology-driven approach; however, the clinical safety needs to be further investigated in an experimental proof-of-concept animal study.

Background and purpose — The long-term results of the 1-or 2-stage revision procedure and infection-free prosthesis survival in a tertiary referral center are unknown. In this retrospective observational study, the long-term results of infection control and infection-free prosthesis survival of the peri-prosthetic joint infection-related 1-and 2-stage revision procedure are evaluated. Furthermore, the merits of performing an antibiotic-free window in the 2-stage revision is evaluated. Patients and methods — All patients who received a 1-or 2-stage revision procedure of the hip or knee between 2010 and 2017 were included. Data was collected on patient and infection characteristics. The primary treatment aim was successful infection control without the use of antibiotic therapy afterwards. Infection-free survival analysis was performed using the Kaplan–Meier method with type of periprosthetic joint infection-related revision as covariate. Within the group of 2-stage revisions, use of an antibiotic-free window was selected as covariate. Results — 128 patients were treated for a periprosthetic joint infection-related revision procedure (81 hips and 47 knees). Successful infection control was achieved in 18 of 21 cases for the 1-stage and 89 out of 107 cases for the 2-stage revision procedure (83%) respectively after follow-up of more than 4 years. In addition, 2-stage revision procedure infection control was achieved in 52 of 60 cases with an anti-biotic-free interval and 37 of 45 cases without such interval (p = 0.6). The mean infection-free survival of the 1-stage revision was 90 months (95% CI 75–105) and 98 months (CI 90–106) for the 2-stage revision procedure. Interpretation — There seems to be no difference in infection control and infection-free survival between the 1-and 2-stage revision procedure. Second, an antibiotic-free window in the case of a 2-stage revision did not seem to influence treatment outcome. However, one must be cautious when interpreting these results due to confounding by indication and the small study population. Therefore, no definite conclusion can be drawn.

The concept of a novel patient-specific 3D-printed shelf implant should be evaluated in a relevant large animal model with hip dysplasia. Therefore, three dogs with radiographic bilateral hip dysplasia and a positive subluxation test underwent unilateral acetabular augmentation with a 3D-printed dog-specific titanium implant. The contralateral side served as control. The implants were designed on CT-based pelvic bone segmentations and extended the dysplastic acetabular rim to increase the weight bearing surface without impairing the range of motion. Outcome was assessed by clinical observation, manual subluxation testing, radiography, CT, and gait analysis from 6 weeks preoperatively until termination at 26 weeks postoperatively. Thereafter, all hip joints underwent histopathological examination. The implantation and recovery from surgery was uneventful. Clinical subluxation tests at the intervention side became negative. Imaging showed medialization of the femoral head at the intervention side and the mean (range) CE-angle increased from 94° (84°-99°) preoperative to 119° (117°-120°) postoperative. Gait analysis parameters returned to pre-operative levels after an average follow-up of 6 weeks. Histology showed a thickened synovial capsule between the implant and the femoral head without any evidence of additional damage to the articular cartilage compared to the control side. The surgical implantation of the 3D shelf was safe and feasible. The patient-specific 3D-printed shelf implants restored the femoral head coverage and stability of dysplastic hips without complications. The presented approach holds promise to treat residual hip dysplasia justifying future veterinary clinical trials to establish clinical effectiveness in a larger cohort to prepare for translation to human clinic.

Cationic host defense peptides (HDPs) are a promising alternative to antibiotics in the fight against Staphylococcus aureus infections. In this study, we investigated the antibacterial and immunomodulatory properties of three HDPs namely IDR-1018, CATH-2, and LL-37. Although all three HDPs significantly inhibited LPS-induced activation of human macrophages, only CATH-2 prevented S. aureus growth. When applied to different infection models focused on intracellularly surviving bacteria, only IDR-1018 showed a consistent reduction in macrophage bacterial uptake. However, this observation did not correlate with an increase in killing the efficiency of intracellular S. aureus. Here, we conclude that despite the promising antibacterial and anti-inflammatory properties of the selected HDPs, macrophages’ intrinsic antibacterial functions were not improved. Future studies should either focus on combining different HDPs or using them synergistically with other antibacterial agents to improve immune cells’ efficacy against S. aureus pathogenesis.

Osteoarthritis of the hip is a painful and debilitating condition commonly occurring in humans and dogs. One of the main causes that leads to hip osteoarthritis is hip dysplasia. Although the current surgical methods to correct dysplasia work satisfactorily in many circumstances, these are associated with serious complications, tissue resorption, and degeneration. In this study, a one-step fabrication of a regenerative hip implant with a patient-specific design and load-bearing properties is reported. The regenerative hip implant is fabricated based on patient imaging files and by an extrusion assisted 3D printing process using a flexible, bone-inducing biomaterial. The novel implant can be fixed with metallic screws to host bone and can be loaded up to physiological loads without signs of critical permanent deformation or failure. Moreover, after exposing the hip implant to accelerated in vitro degradation, it is confirmed that it is still able to support physiological loads even after losing ≈40% of its initial mass. In addition, the osteopromotive properties of the novel hip implant is demonstrated as shown by an increased expression of osteonectin and osteocalcin by cultured human mesenchymal stem cells after 21 days. Overall, the proposed hip implant provides an innovative regenerative and mechanically stable solution for hip dysplasia treatment.

Introduction: Debridement, antibiotics and implant retention (DAIR) procedures are effective treatments for acute postoperative or acute hematogenous periprosthetic joint infections. However, literature reporting on the effectiveness of DAIR procedures performed after a one- or two-stage revision because of a prosthetic joint infection (PJI) (PJI-related revision arthroplasty) is scarce. The aim of this study is to retrospectively evaluate the infection control after 1 year of a DAIR procedure in the case of an early postoperative infection either after primary arthroplasty or after PJI-related revision arthroplasty. Materials and methods: All patients treated with a DAIR procedure within 3 months after onset of PJI between 2009 and 2017 were retrospectively included. Data were collected on patient and infection characteristics. All infections were confirmed by applying the Musculoskeletal Infection Society (MSIS) 2014 criteria. The primary outcome was successful control of infection at 1 year after a DAIR procedure, which was defined as the absence of clinical signs, such as pain, swelling, and erythema; radiological signs, such as protheses loosening; or laboratory signs, such as C-reactive protein (CRP) (<10) with no use of antibiotic therapy. Results: Sixty-seven patients were treated with a DAIR procedure (41 hips and 26 knees). Successful infection control rates of a DAIR procedure after primary arthroplasty (n=51) and after prior PJI-related revision arthroplasty (n=16) were 69 % and 56 %, respectively (p=0.38). The successful infection control rates of a DAIR procedure after an early acute infection (n=35) and after a hematogenous infection (n=16) following primary arthroplasty were both 69 % (p=1.00). Conclusion: In this limited study population, no statistically significant difference is found in infection control after 1 year between DAIR procedures after primary arthroplasty and PJI-related revision arthroplasty.

Additive manufacturing has facilitated fabrication of complex and patient-specific metallic meta-biomaterials that offer an unprecedented collection of mechanical, mass transport, and biological properties as well as a fully interconnected porous structure. However, applying meta-biomaterials for addressing unmet clinical needs in orthopedic surgery requires additional surface functionalities that should be induced through tailor-made coatings. Here, we developed multi-functional layer-by-layer coatings to simultaneously prevent implant-associated infections and stimulate bone tissue regeneration. We applied multiple layers of gelatin- and chitosan-based coatings containing either bone morphogenetic protein (BMP)-2 or vancomycin on the surface of selective laser melted porous structures made from commercial pure Titanium (CP Ti) and designed using a triply periodic minimal surface (i.e., sheet gyroid). The additive manufacturing process resulted in a porous structure and met the the design values comparatively. X-ray photoelectron spectroscopy spectra confirmed the presence and composition of the coating layers. The release profiles showed a continued release of both vancomycin and BMP-2 for 2–3 weeks. Furthermore, the developed meta-biomaterials exhibited a very strong antibacterial behavior with up to 8 orders of magnitude reduction in both planktonic and implant-adherent bacteria and no signs of biofilm formation. The osteogenic differentiation of mesenchymal stem cells was enhanced, as shown by two-fold increase in the alkaline phosphatase activity and up to four-fold increase in the mineralization of all experimental groups containing BMP-2. Eight-week subcutaneous implantation in vivo showed no signs of a foreign body response, while connective tissue ingrowth was promoted by the layer-by-layer coating. These results unequivocally confirm the superior multi-functional performance of the developed biomaterials.

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.

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.

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.

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.