Aims. This study intended to investigate the effect of vericiguat (VIT) on titanium rod osseointegration in aged rats with iron overload, and also explore the role of VIT in osteoblast and osteoclast differentiation. Methods. In this study, 60 rats were included in a titanium rod implantation model and underwent subsequent guanylate cyclase treatment. Imaging, histology, and biomechanics were used to evaluate the osseointegration of rats in each group. First, the impact of VIT on bone integration in aged rats with iron overload was investigated. Subsequently, VIT was employed to modulate the differentiation of MC3T3-E1 cells and RAW264.7 cells under conditions of iron overload. Results. Utilizing an OVX rat model, we observed significant alterations in bone mass and osseointegration due to VIT administration in aged rats with iron overload. The observed effects were concomitant with reductions in bone metabolism, oxidative stress, and inflammation. To elucidate whether these effects are associated with osteoclast and osteoblast activity, we conducted in vitro experiments using MC3T3-E1 cells and RAW264.7 cells. Our findings indicate that iron accumulation suppressed the activity of MC3T3-E1 while enhancing RAW264.7 function. Furthermore, iron overload significantly decreased oxidative stress levels; however, these detrimental effects can be mitigated by VIT treatment. Conclusion. Collectively, our data provide compelling evidence that VIT has the potential to reverse the deleterious consequences of iron overload on osseointegration and bone mass during ageing. Cite this article: Bone Joint Res 2024;13(9):427–440

Aims. To develop an early implant instability murine model and explore the use of intermittent parathyroid hormone (iPTH) treatment for initially unstable implants. Methods. 3D-printed titanium implants were inserted into an oversized drill-hole in the tibiae of C57Bl/6 mice (n = 54). After implantation, the mice were randomly divided into three treatment groups (phosphate buffered saline (PBS)-control, iPTH, and delayed iPTH). Radiological analysis, micro-CT (µCT), and biomechanical pull-out testing were performed to assess implant loosening, bone formation, and osseointegration. Peri-implant tissue formation and cellular composition were evaluated by histology. Results. iPTH reduced radiological signs of loosening and led to an increase in peri-implant bone formation over the course of four weeks (timepoints: one week, two weeks, and four weeks). Observational histological analysis shows that iPTH prohibits the progression of fibrosis. Delaying iPTH treatment until after onset of peri-implant fibrosis still resulted in enhanced osseointegration and implant stability. Despite initial instability, iPTH increased the mean pull-out strength of the implant from 8.41 N (SD 8.15) in the PBS-control group to 21.49 N (SD 10.45) and 23.68 N (SD 8.99) in the immediate and delayed iPTH groups, respectively. Immediate and delayed iPTH increased mean peri-implant bone volume fraction (BV/TV) to 0.46 (SD 0.07) and 0.34 (SD 0.10), respectively, compared to PBS-control mean BV/TV of 0.23 (SD 0.03) (PBS-control vs immediate iPTH, p < 0.001; PBS-control vs delayed iPTH, p = 0.048; immediate iPTH vs delayed iPTH, p = 0.111). Conclusion. iPTH treatment mediated successful osseointegration and increased bone mechanical strength, despite initial implant instability. Clinically, this suggests that initially unstable implants may be osseointegrated with iPTH treatment. Cite this article: Bone Joint Res 2022;11(5):260–269

Aims. This study examined whether systemic administration of melatonin would have different effects on osseointegration in ovariectomized (OVX) rats, depending on whether this was administered during the day or night. Methods. In this study, a titanium rod was implanted in the medullary cavity of one femoral metaphysis in OVX rats, and then the rats were randomly divided into four groups: Sham group (Sham, n = 10), OVX rat group (OVX, n = 10), melatonin day treatment group (OVX + MD, n = 10), and melatonin night treatment group (OVX + MN, n = 10). The OVX + MD and OVX + MN rats were treated with 30 mg/kg/day melatonin at 9 am and 9 pm, respectively, for 12 weeks. At the end of the research, the rats were killed to obtain bilateral femora and blood samples for evaluation. Results. Micro-CT and histological evaluation showed that the bone microscopic parameters of femoral metaphysis trabecular bone and bone tissue around the titanium rod in the OVX + MD group demonstrated higher bone mineral density, bone volume fraction, trabecular number, connective density, trabecular thickness, and lower trabecular speculation (p = 0.004) than the OVX + MN group. Moreover, the biomechanical parameters of the OVX + MD group showed higher pull-out test and three-point bending test values, including fixation strength, interface stiffness, energy to failure, energy at break, ultimate load, and elastic modulus (p = 0.012) than the OVX + MN group. In addition, the bone metabolism index and oxidative stress indicators of the OVX + MD group show lower values of Type I collagen cross-linked C-telopeptide, procollagen type 1 N propeptide, and malondialdehyde (p = 0.013), and higher values of TAC and SOD (p = 0.002) compared with the OVX + MN group. Conclusion. The results of our study suggest that systemic administration with melatonin at 9 am may improve the initial osseointegration of titanium rods under osteoporotic conditions more effectively than administration at 9 pm. Cite this article: Bone Joint Res 2022;11(11):751–762

Introduction. Approximately 2,000 Skeletal transcutaneous osseointegration (STOI) procedures have been performed worldwide as of 2020, more than half of which have been performed by the Osseointegration Group of Australia using a press-fit technique with either ILP or OPL implant designs. Despite the consistently demonstrated clinical benefits, concerns regarding potential complications following STOI have slowed its widespread adoption. As more patients are followed for a longer period of time, longitudinal studies have confirmed complication rates are very acceptable, similar to those of total ankle and total elbow replacements. One of the major risk category is implant removal. The primary goal of this study was to investigate the complications and technical issues associated with transtibial osseointegration implant removal due to any cause. The focus here will be on the press-fit ILP and OPL implants, including the indications for removal and patient outcomes following removal. Materials & Methods. A review of our osseointegration registry between November 2010 and March 2022 was performed. Inclusion criteria were patients who have undergone removal of a transtibial osseointegration implant due to any cause. Selected patients either had a follow-up of at least two years or had their index osseointegration surgery at least two years prior to when the study was performed. Patients who have had osseointegration at other anatomic levels, and patients who underwent simultaneous total knee replacement with transtibial osseointegration were excluded from the registry search. Results. There were a total of 148 transtibial osseointegration procedures performed during the study period, with 97 (65.5%) performed in males and 51 (34.5%) performed in females. The average age at first stage osseointegration procedure is 50.4 years (range 16.8–87.9, SD 14.1). In the study cohort of 22 cases requiring implant removals, 12 (54.5%) were male and 10 (45.5%) were female. The average age at first stage osseointegration procedure in this cohort is 51.3 (range 37.4–82.6, SD 10.7) and average BMI 30.3 (range 21.9–40.9, SD 5.8). Although men comprised the majority of removals, women had a greater relative risk (Fisher exact test p=0.032). The average duration from time of STOI to removal was 2.6 years (range 0.1–6.8, SD 1.9) within this 11.5 year follow-up period. The most frequent indication was infection (54.6%, n=12) followed equally by pain (13.6%, n=3), aseptic loosening (13.6%, n=3) and implant fracture (13.6%, n=3), and lastly failure to integrate (4.6%, n=1). Conclusions. Of the 22 removals, 12 were reimplanted at the same anatomical level (10 were reimplanted within 6 months, 1 within 12 months, and 1 within 24 months). 11 of these cases currently wear their prosthetic legs for more than 13 hours daily. 1 case was recently reimplanted and still completing their loading program. Of the patients who were not reimplanted at the same anatomical level, 1 required proximal amputation with transfemoral osseointegration. 3 patients converted to traditional socket prostheses (TSP) due to pain, and 1 underwent proximal amputation and converted to TSP due to infection. 3 cases are currently awaiting transtibial osseointegration reimplantation, and 1 patient was deceased. 1 patient was lost to follow-up

Introduction. Percutaneous EndoProsthetic Osseointegration for Limbs (PEPOL) facilitates improved quality of life (QOL) and objective mobility for most amputees discontent with their traditional socket prosthesis (TSP) experience. Some amputees desiring PEPOL have residual bone much shorter than the currently marketed press-fit implant lengths of 14–16 cm, potentially a risk for failure to integrate. We report on the techniques used, complications experienced, the management of those complications, and the overall mobility outcomes of seven patients who had femur distraction osteogenesis (DO) with a Freedom nail followed by PEPOL. Materials & Methods. Retrospective evaluation of a prospectively maintained database identified nine patients (5 females) who had transfemoral DO in preparation for PEPOL with two years of follow-up after PEPOL. Six patients had traumatic causes of amputation, one had perinatal complications, one was performed to manage necrotizing fasciitis and one was performed as a result of osteosarcoma. Results. The average age at which DO commenced was 39.4±15.9 years, and seven patients had their amputation more than ten years prior (average 25.5±18.8 years). The residual femurs on average started at 102.2±39.7 mm and were lengthened 58.1±20.7 mm, 98±45% of goal (99±161% of the original bone length). Five patients (56%) had a complication requiring additional surgery: four events of inadequate regenerate were managed with continued lengthening to desired goal followed by autograft placement harvested from contralateral femur reaming; one patient had the cerclage wires break which required operative replacement. All patients had osseointegration performed, at 355±123 days after the initial lengthening nail surgery. One patient had K-level >2 before DO, at a mean of 3.4±0.6 (2.6–4.4) years following osseointegration six patients had K-level >2. The 6 Minute Walk Test remained unchanged (267±56 vs 308 ± 117 meters). Patient self-rating of prosthesis function, problems, and amputee situation did not significantly change from before DO to after osseointegration. Six patients required additional surgery following osseointegration: six to remove fixation plates placed to maintain distraction osteogenesis length at osseointegration; two required irritation and debridement for infection. Conclusions. Extremely short residual femurs which make TSP use troublesome can be lengthening with externally controlled telescoping nails, and successfully achieve osseointegration. However, it is imperative to counsel patients that additional surgery to address inadequate regenerate or to remove painful hardware used to maintain fixation may be necessary. This may improve the amputee's expectations before beginning on a potentially arduous process

Aims. Hydroxyapatite (HA)-coated collars have been shown to reduce aseptic loosening of massive endoprostheses following primary surgery. Limited information exists about their effectiveness in revision surgery. The aim of this study was to radiologically assess osteointegration to HA-coated collars of cemented massive endoprostheses following revision surgery. Methods. Retrospective review of osseointegration frequency, pattern, and timing to a specific HA-coated collar on massive endoprostheses used in revision surgery at our tertiary referral centre between 2010 to 2017 was undertaken. Osseointegration was radiologically classified on cases with a minimum follow-up of six months. Results. In all, 39 patients underwent radiological review at mean 43.5 months; 22/39 (56.4%) showed no osseointegration to the collar. Revision endoprostheses for aseptic loosening were less likely to show osseointegration compared with other indications for revision. Oncological cases with previous or current infection were more likely to show osseointegration to ≥ 1 collar side than those without evidence of prior infection. Conclusion. This seven-year review identified osseointegration of HA-coated collars after revision surgery is less likely (43.6%, 17/39) than after primary surgery. Young patients who undergo revision surgery following initial oncological indication may benefit the most from this collar design. Use in revision oncological cases with a history of infection may be beneficial. HA-coated collars showed limited benefit for patients undergoing revision for failed arthroplasty with history of infection. Cite this article: Bone Jt Open 2021;2(6):371–379

Percutaneous EndoProsthetic Osseointegration for Limbs (PEPOL) facilitates improved quality of life (QOL) and objective mobility for most amputee's discontent with their traditional socket prosthesis (TSP) experience. Some amputees desiring PEPOL have residual bone much shorter than the currently marketed press-fit implant lengths of 14-16 cm, potentially a risk for failure to integrate. We report on the techniques used, complications experienced, the management of those complications, and the overall mobility outcomes of seven patients who had femur distraction osteogenesis (DO) with a Freedom nail followed by PEPOL. Retrospective evaluation of a prospectively maintained database identified nine patients (5 females) who had transfemoral DO in preparation for PEPOL with two years of follow-up after PEPOL. Six patients had traumatic causes of amputation, one had perinatal complications, one was performed to manage necrotizing fasciitis and one was performed as a result of osteosarcoma. The residual femurs on average started at 102.2±39.7 mm and were lengthened 58.1±20.7 mm, 98±45% of goal (99±161% of the original bone length). Five patients (56%) had a complication requiring additional surgery. At a mean of 3.4±0.6 (2.6-4.4) years following osseointegration six patients had K-level >2. The 6 Minute Walk Test remained unchanged (267±56 vs 308 ± 117 meters). Patient self-rating of prosthesis function, problems, and amputee situation did not significantly change from before DO to after osseointegration. Six patients required additional surgery following osseointegration: six to remove fixation plates placed to maintain distraction osteogenesis length at osseointegration; two required irritation and debridement for infection. Extremely short residual femurs which make TSP use troublesome can be lengthening with externally controlled telescoping nails, and successfully achieve osseointegration. However, it is imperative to counsel patients that additional surgery to address inadequate regenerate or to remove painful hardware used to maintain fixation may be necessary. This may improve the amputee's expectations before beginning on a potentially arduous process

Aims. The main advantage of 3D-printed, off-the-shelf acetabular implants is the potential to promote enhanced bony fixation due to their controllable porous structure. In this study we investigated the extent of osseointegration in retrieved 3D-printed acetabular implants. Methods. We compared two groups, one made via 3D-printing (n = 7) and the other using conventional techniques (n = 7). We collected implant details, type of surgery and removal technique, patient demographics, and clinical history. Bone integration was assessed by macroscopic visual analysis, followed by sectioning to allow undecalcified histology on eight sections (~200 µm) for each implant. The outcome measures considered were area of bone attachment (%), extent of bone ingrowth (%), bone-implant contact (%), and depth of ingrowth (%), and these were quantified using a line-intercept method. Results. The two groups were matched for patient sex, age (61 and 63 years), time to revision (30 and 41 months), implant size (54 mm and 52 mm), and porosity (72% and 60%) (p > 0.152). There was no difference in visual bony attachment (p = 0.209). Histological analysis showed greater bone ingrowth in 3D-printed implants (p < 0.001), with mean bone attachment of 63% (SD 28%) and 37% (SD 20%), respectively. This was observed for all the outcome measures. Conclusion. This was the first study to investigate osseointegration in retrieved 3D-printed acetabular implants. Greater bone ingrowth was found in 3D-printed implants, suggesting that better osseointegration can be achieved. However, the influence of specific surgeon, implant, and patient factors needs to be considered. Cite this article: Bone Joint Res 2021;10(7):388–400

Introduction. Transtibial osseointegration (TFOI) for amputees has limited but clear literature identifying superior quality of life and mobility versus a socketed prosthesis. Some amputees have knee arthritis that would be relieved by a total knee replacement (TKR). No other group has reported performing a TKR in association with TTOI (TKR+TTOI). We report the outcomes of nine patients who had TKR+TTOI, followed for an average 6.5 years. Materials & Methods. Our osseointegration registry was retrospectively reviewed to identify all patients who had TTOI and who also had TKR, performed at least two years prior. Four patients had TKR first the TTOI, four patients had simultaneous TKR+TTOI, and one patient had 1 OI first then TKR. All constructs were in continuity from hinged TKR to the prosthetic limb. Outcomes were: complications prompting surgical intervention, and changes in daily prosthesis wear hours, Questionnaire for Persons with a Transfemoral Amputation (QTFA), and Short Form 36 (SF36). All patients had clinical follow-up, but two patients did not have complete survey and mobility tests at both time periods. Results. Six (67%) were male, average age 51.2±14.7 years. All primary amputations were performed to manage traumatic injury or its sequelae. No patients died. Five patients (56%) developed infection leading to eventual transfemoral amputation 36.0±15.3 months later, and 1 patient had a single debridement six years after TTOI with no additional surgery in the subsequent two years. All patients who had transfemoral amputation elected for and received transfemoral osseointegration, and no infections occurred, although one patient sustained a periprosthetic fracture which was managed with internal fixation and implant retention and walks independently. The proportion of patients who wore their prosthesis at least 8 hours daily was 5/9=56%, versus 7/9=78% (p=.620). Even after proximal level amputation, the QTFA scores improved versus prior to TKR+TTOI, although not significantly: Global (45.2±20.3 vs 66.7±27.6, p=.179), Problem (39.8±19.8 vs 21.5±16.8, p=.205), Mobility (54.8±28.1 vs 67.7±25.0, p=.356). SF36 changes were also non-significant: Mental (58.6±7.0 vs 46.1±11.0, p=.068), Physical (34.3±6.1 vs 35.2±13.7, p=.904). Conclusions. TKR+TTOI presents a high risk for eventual infection prompting subsequent transfemoral amputation. Although none of these patients died, in general, TKR infection can lead to patient mortality. Given the exceptional benefit to preserving the knee joint to preserve amputee mobility and quality of life, it would be devastating to flatly force transtibial amputees with severe degenerative knee joint pain and unable to use a socket prosthesis to choose between TTOI but a painful knee, or preemptive transfemoral amputation for transfemoral osseointegration. Therefore, TTOI for patients who also request TKR must be considered cautiously. Given that this frequency of infection does not occur in patients who have total hip replacement in association with transfemoral osseointegration, the underlying issue may not be that linked joint replacement with osseointegrated limb replacement is incompatible, but may require further consideration of biological barriers to ascending infection and/or significant changes to implant design, surgical technique, or other yet-uncertain factors

Aims. Osseointegrated prosthetic limbs allow better mobility than socket-mounted prosthetics for lower limb amputees. Fractures, however, can occur in the residual limb, but they have rarely been reported. Approximately 2% to 3% of amputees with socket-mounted prostheses may fracture within five years. This is the first study which directly addresses the risks and management of periprosthetic osseointegration fractures in amputees. Methods. A retrospective review identified 518 osseointegration procedures which were undertaken in 458 patients between 2010 and 2018 for whom complete medical records were available. Potential risk factors including time since amputation, age at osseointegration, bone density, weight, uni/bilateral implantation and sex were evaluated with multiple logistic regression. The mechanism of injury, technique and implant that was used for fixation of the fracture, pre-osseointegration and post fracture mobility (assessed using the K-level) and the time that the prosthesis was worn for in hours/day were also assessed. Results. There were 22 periprosthetic fractures; they occurred exclusively in the femur: two in the femoral neck, 14 intertrochanteric and six subtrochanteric, representing 4.2% of 518 osseointegration operations and 6.3% of 347 femoral implants. The vast majority (19/22, 86.4%) occurred within 2 cm of the proximal tip of the implant and after a fall. No fractures occurred spontaneously. Fixation most commonly involved dynamic hip screws (10) and reconstruction plates (9). No osseointegration implants required removal, the K-level was not reduced after fixation of the fracture in any patient, and all retained a K-level of ≥ 2. All fractures united, 21 out of 22 patients (95.5%) wear their osseointegration-mounted prosthetic limb longer daily than when using a socket, with 18 out of 22 (81.8%) reporting using it for ≥ 16 hours daily. Regression analysis identified a 3.89-fold increased risk of fracture for females (p = 0.007) and a 1.02-fold increased risk of fracture per kg above a mean of 80.4 kg (p = 0.046). No increased risk was identified for bilateral implants (p = 0.083), time from amputation to osseointegration (p = 0.974), age at osseointegration (p = 0.331), or bone density (g/cm2, p = 0.560; T-score, p = 0.247; Z-score, p = 0.312). Conclusion. The risks and sequelae of periprosthetic fracture after press-fit osseointegration for amputation should not deter patients or clinicians from considering this procedure. Females and heavier patients are likely to have an increased risk of fracture. Age, years since amputation, and bone density do not appear influential. Cite this article: Bone Joint J 2020;102-B(2):162–169

Failure of osseointegration and periprosthetic joint infection (PJI) are the two main reasons of implant failure after total joint replacement (TJR). Nanofiber (NF) implant surface coating represents an alternative local drug eluting device that improves osseointegration and decreases the risk of PJI. The purpose of this study was to investigate the therapeutic efficacies of erythromycin (EM)-loaded coaxial PLGA/PCL-PVA NF coating in a rat S. aureus-infected tibia model. NF coatings with 100mg and 1000mg EM were prepared. NF without EM was included as positive control. 56 Sprague Dawley rats were divided into 4 groups. A titanium pin (1.0-mm x 8 mm) was placed into the tibia through the intercondylar notch. S. aureus (SA) was introduced by both direct injection of 10 μl broth (1 × 10. 4. CFU) into the medullary cavity and single dip of Ti pins into a similar solution prior to insertion. Rats were sacrificed at 8 and 16 weeks after surgery. The outcome measurements include μCT based quantitative osteolysis evaluation and hard tissue histology. Results: EM-NF coating (EM100 and EM1000) reduced osteolysis at 8 and 16 weeks, compared to EM0 and negative control. The effective infection control by EM-NFs was further confirmed by hard tissue section analysis. The Bone implant contact (BIC) and bone area fraction Occupancy (BAFO) within 200 µm of the surface of the pins were used to evaluate the osseointegration and new bone formation around the implants. At 16 weeks, the bone implant contact (BIC) of EM 100 (35.08%) was higher than that of negative control (3.43%) and EM0 (0%). The bone area fraction occupancy within 200 µm (BAFO) of EM100 (0.63 mm2) was higher than that of negative control (0.390 mm2) and EM0 (0.0 mm. 2. ). The BAFO of EM100 was also higher than that of EM1000 (0.3mm. 2. ). There was much less osteolysis observed with EM100 and EM1000 NF coatings at 16 weeks, as compared to EM0 positive control, p=0.08 and p=0.1, respectively. Osseointegration and periprosthetic bone formation was enhanced by EM-NFs, especially EM100. Data from this pilot study is promising for improving implant surface fabrication strategies

Traditional socket prosthesis (TSP) rehabilitation for amputees is associated with substantial dissatisfaction due to poor mobility and pain from soft tissue squeezing. Osseointegration (OI), eliminates skin compression and prosthesis fit issues, providing superior mobility and quality of life (QOL) for most amputees. The potential for OI to benefit patients with exceptionally poor mobility is understudied. To address this knowledge gap, this project investigated the mobility and QOL changes. A retrospective review was performed to identify transfemoral amputees who presented with wheelchair-bound mobility (K0) and had at least five years of post-osseointegration follow-up. Outcome measures included changes in mobility (K-level, daily prosthesis wear hours, Timed Up and Go (TUG), 6 minute walk test (6MWT)) and QOL (Questionnaire for persons with a Transfemoral Amputation (QTFA); Short Form Health Survey 36 (SF36). Adverse events recorded included debridement for infection, implant revision surgery, fractures, and implant failures. 9 patients with mean age 48.2±7.7 (range 34-59) years were included. The proportion of patients achieving K-level >2 improved from 0/9=0% to [9/9=100%], p<0.001. The 6MWT improved from 0±0 to 320.65±57 meters (p<0.001). The TUG improved from incapable to 10.68±2.7 seconds (p<0.001). Statistically significant QOL metrics included QTFA global score (33.33±31 vs 68.52±21, p=0.039), SF36 physical component score (30.03±6.3 vs 42.34±12, p=0.023) and the SF36 mental component score (47.89±8.8 vs 51.95±10.4, p=0.332). Six patients required operative intervention to address complications. Five developed infections: three had debridement, and 2 required implant removal and reimplantation. Osseointegration does confer significant sustained mobility and quality of life improvement for wheelchair bound transfemoral amputees. All 9 K0 patients had statistically improved mobility and QOL after osseointegrated reconstruction. This supports osseointegration as an effective rapid and long-term rehabilitation alternative for patients who have the neurologic and muscular capacity to walk but are unable due to issues related to their TSP

The use of implant biomaterials for prosthetic reconstructive surgery and osteosynthesis is consolidated in the orthopaedic field, improving the quality of life of patients and allowing for healthy and better ageing. However, there is the lack of advanced innovative methods to investigate the potentialities of smart biomaterials, particularly for the study of local effects of implant and osteointegration. Despite the complex process of osseointegration is difficult to recreate in vitro, the growing challenges in developing alternative models require to set-up and validate new approaches. Aim of the present study is to evaluate an advanced in vitro tissue culture model of osteointegration of titanium implants in human trabecular bone. Cubic samples (1.5×1.5 cm) of trabecular bone were harvested as waste material from hip arthroplasty surgery (CE AVEC 829/2019/Sper/IOR); cylindrical defects (2 mm Ø, 6 mm length) were created, and tissue specimens assigned to the following groups: 1) empty defects- CTR-; 2) defects implanted with a cytotoxic copper pin (Merck cod. 326429)- CTR+; 3) defects implanted with standard titanium pins of 6 µm-rough (ZARE S.r.l) -Ti6. Tissue specimens were cultured in mini rotating bioreactors in standard conditions, weekly assessing viability. At the 8-week-timepoint, immunoenzymatic, microtomographic, histological and histomorphometric analyses were performed. The model was able to simulate the effects of implantation of the materials, showing a drop in viability in CTR+, differently from Ti6 which appears to have a trophic effect on the bone. MicroCT and histological analysis supported the results, with lower BV/TV and Tb.Th values observed in CTR- compared to CTR+ and Ti6 and signs of matrix and bone deposition at the implant site. The collected data suggest the reliability of the tested model which can recreate the osseointegration process in vitro and can therefore be used for preliminary evaluations to reduce and refine in vivo preclinical models. Acknowledgment: This work was supported by Emilia-Romagna Region for the project “Sviluppo di modelli biologici in vitro ed in silico per la valutazione e predizione dell'osteointegrazione di dispositivi medici da impianto nel tessuto osseo”

Introduction. The use of osseointegrated limb replacement prostheses for amputees are rapidly growing in popularity due to the many benefits over conventional sockets. Many institutions worldwide are beginning to provide this surgical option to their patients and are advertising the service online. The aim of this study was to assess the quality and reading level of related information available online. Materials & Methods. A search was performed using the 3 most popular English language search engines reviewing the top 40 websites from each, using the term osseointegration on. Duplicates, videos, medical journal articles and dentistry websites were excluded. All included websites were assessed for reading using the FKGL, G-Fog and FRE. Quality was assessed using the JAMA benchmark criteria, HONC erificate and a novel 16-point scoring system developed specifically for limb replacement osseointegration. Results. The search resulted in 9,985,000 websites, 120 were assessed. 23 websites were included after removal of duplicates, medical journals and dentistry websites. None with reading grades of 6 or lower. Mean FKGL grade was 11.3/18. Mean FRE was 38.83/100. Mean G-FOG was 12.57/20. No websites had HONC. Mean JAMA score was 1.76/4. Mean HSSOIS was 5.70/16. Most provided information on indications(16/23) and explanation of osseointegration 17/23) but few discussed costs(3/23) or restrictions(9/23). Conclusions. There is already a large amount of information available online regarding osseointegrated prostheses. However, the most accessible information may exceed most patients’ reading levels, limiting is usefulness. Further, the information available is generally of low quality, The quality of information and the readability of online content should be improved to ensure more effective patient education

Introduction. Transfemoral osseointegration (TFOI) for amputees has substantial literature proving superior quality of life and mobility versus a socketed prosthesis. Some amputees have hip arthritis that would be relieved by a total hip replacement (THR). No other group has reported performing a THR in association with TFOI (THR+TFOI). We report the outcomes of eight patients who had THR+TFOI, followed for an average 5.2 years. Materials & Methods. Our osseointegration registry was retrospectively reviewed to identify all patients who had TFOI and also had THR, performed at least two years prior. Six patients had TFOI then THR, one simultaneous, one THR then TFOI. All constructs were in continuity from hip to prosthetic limb. Outcomes were: complications prompting surgical intervention, and changes in subjective hip pain, K-level, daily prosthesis wear hours, Questionnaire for Persons with a Transfemoral Amputation (QTFA), and Short Form 36 (SF36). All patients had clinical follow-up, but one patient did not have complete mobility and quality of life survey data at both time periods. Results. Four (50%) were male, average age 52.7±14.8 years. Three patients (38%) had amputation for trauma, three for osteosarcoma, one each (13%) infected total knee and persistent infection after deformity surgery. One patient died one year after THR+TOFA from subsequently diagnosed pancreatic cancer. One patient had superficial debridement for infection with implant retention after five years. No implants were removed, no fractures occurred. All patients reported severe hip pain preoperatively versus full relief of hip pain afterwards. K-level improved from 0/8=0% K>2 (six were wheelchair-bound) to 5/8=63% (p=.026). At least 8 hours of prosthesis wear was reported by 2/7=29% before TOFA vs 5/7=71% after (p=.286). The QTFA improved in all categories, but not significantly: Global (40.0±21.6 vs 60.0±10.9, p=.136), Problem (50.2±33.2 vs 15.4±8.4, p=.079), and Mobility (35.9±26.8 vs 58.3±30.7, p=.150). The SF36 also improved minimally and not significantly: Mental (53.6±12.0 vs 54.7±4.6, p=.849) and Physical (32.5±10.9 vs 36.3±11.2, p=.634). Conclusions. THR+TFOI is a successful reconstruction option for amputees who desire relief from severe pain related to hip joint degeneration, and also the opportunity for improved mobility and quality of life that TFOI typically confers. In our cohort, the procedure proved safe: no associated deaths, no removals, one soft tissue debridement. Mobility improved markedly. Quality of life improved, but not to significant thresholds as measured by the surveys. THR+TFOI appears safe and reasonable to offer to transfemoral amputees with painful hip joint degeneration

Objectives. Ultraviolet (UV) light-mediated photofunctionalisation is known to improve osseointegration of pure titanium (Ti). However, histological examination of titanium alloy (Ti6Al4V), which is frequently applied in orthopaedic and dental surgery, has not yet been performed. This study examined the osseointegration of photofunctionalised Ti6Al4V implants. Methods. Ti and Ti6Al4V implants were treated with UV light, and the chemical composition and contact angle on the surfaces were evaluated to confirm photofunctionalisation. The implants were inserted into femurs in rats, and the rats were killed two or four weeks after the surgery. For histomorphometric analysis, both the bone–implant contact (BIC) ratio and the bone volume (BV) ratio were calculated from histological analysis and microcomputed tomography data. Results. The amount of carbon and the contact angle on both implants were significantly reduced after UV irradiation. The BIC ratios for both UV light-treated implants significantly increased at two weeks, but there was no significant difference at four weeks. There was no significant difference in the BV ratios between the UV light-treated and control implants at two or four weeks. Conclusions. This study suggests that photofunctionalisation of Ti6Al4V implants, similar to that of Ti implants, may promotes osseointegration in early but not in the late phase of osseointegration. Cite this article: R. Yamauchi, T. Itabashi, K. Wada, T. Tanaka, G. Kumagai, Y. Ishibashi. Photofunctionalised Ti6Al4V implants enhance early phase osseointegration. Bone Joint Res 2017;6:331–336. DOI: 10.1302/2046-3758.65.BJR-2016-0221.R1

3D Printed polyether-ether-ketone (PEEK) has gained widespread use in clinical practice due to its excellent biocompatibility, biomechanical compatibility, and personalization. However, pre-printed PEEK implants are not without their flaws, including bioinert, optimization distortion of 3D printing digital model and prosthetic mismatching. Recent advancements in mechanical processing technology have made it possible to print bone implants with PEEK fused deposition, allowing for the construction of mechanically adaptable implants. In this study, we aimed to synthesize silanized polycitrate (PCS) via thermal polymerization and in situ graft it to PEEK surface to construct an elastomer coating for 3D printed PEEK implants (PEEK-PCS). This incorporation of PCS allows the implant to exhibit adaptive space filling ability and stress dispersal. In vivo and in vitro results, PEEK-PCS exhibited exceptional osseointegration and osteogenesis properties along with macrophage M2 phenotypic polarization, inflammatory factors reducing, promotion of osteogenic differentiation in bone marrow mesenchymal stem cells (BMSCs). Additionally, PEEK-PCS displays good autofluorescence properties in vitro and in vivo, with stable fluorescence for 14 days, suggesting potential bioimaging applications. The study confirms that PEEK in situ grafting with thermo-polymerized PCS elastomers is a viable approach for creating multifunctional (bone defect adaptation, bioimaging, immune regulation, and osseointegration) implants for bone tissue engineering

Introduction. Patients with aseptic loosening, a cause of failure in uncemented total joint arthroplasty (TJA), often present with fibrous tissue at the bone-implant interface. 1. In this study, we characterize the presence of neutrophil extracellular traps (NETs) in the intramedullary fibrotic membrane of aseptic loosening patients. We further explore the role of NETs, mediated by peptidyl arginine deiminase (PAD4), in peri-implant fibrosis and osseointegration failure through a murine model of unstable tibial implantation. 2–4. Methods. Peri-implant membrane was retrieved from five patients during total hip revision surgery and analyzed for the presence of NETs (citH3+ with extracellular DNA) via immunofluorescence. A Ti-6Al-4V implant was inserted in an oversized drill-hole in the right proximal tibia of 8-week-old C57BL/6J and PAD4 knockout mice (n=3 per group). Fourteen days later, all mice were euthanized, and implanted tibias were dissected. Fibrosis and osseointegration at the bone-implant interface were assessed by micro-computed tomography (microCT) and hematoxylin and eosin (H&E) staining. H&E samples were scored blindly by the investigator and another observer for signs of poor (score=0) to excellent osseointegration (score=3) using a rubric established in our lab. Results. NETs were found in peri-implant membrane collected from aseptic loosening patients (Figure 1a) and at the bone-implant interface in a murine model (Figure 1b). Unstable implants in wild type mice failed to osseointegrate, indicated by presence of fibroblast-like cells (dashed arrow), immature bone matrix (Figure 1c), low bone volume fraction (BV/TV) and bone surface area (BS) (Figure 1e). Unstable implants in PAD4. −/−. mice showed signs of good osseointegration such as mature trabeculae (solid arrow) (Figure 1d), higher BV/TV (p<0.10) and BS (p<0.05) (Figure 1f). Histological osseointegration scoring indicated wildtype mice exhibited an average score of 0.83 and PAD4. −/−. exhibited an average score of 2.5 (p<0.05, weighted Cohen's kappa = 0.714) (Figure 1g). Conclusion. NETs were characterized in fibrotic tissue in both aseptic loosening patients and in a murine model of unstable tibial implantation. NET inhibition was able to successfully prevent peri-implant fibrosis and osseointegration failure, leading the way for a potential novel non-invasive therapeutic approach for the treatment of aseptic loosening. For any figures, tables, or references, please contact the authors directly

Due to unsatisfactory results and reported drawbacks of anterior cruciate ligament (ACL) reconstruction new regenerative approaches based on tissue-engineering strategies are currently under investigation. It was the purpose of this study to determine if a novel silk fiber-based ACL scaffold is able to initiate osteointegration in the femoral and tibial bone tunnels under in vivo conditions. Furthermore we tested if the osteointegration process will be improved by intraoperatively seeding the scaffolds with the autologous stromal vascular fraction, an adipose-derived, stem cell-rich isolate from knee fat pads. In this controlled laboratory study, 33 sheep underwent ACL resection and were then randomly assigned to 2 experimental groups: ACL reconstruction with a scaffold alone and ACL reconstruction with a cell-seeded scaffold. Half of the sheep in each group were randomly chosen and euthanized 6 months after surgery and the other half at 12 months. To analyze the integration of the silk-based scaffold in the femoral and tibial bone tunnels, hard tissue histology and micro-computed tomography measurements were performed. The histological workup showed that in all treatment groups, with or without the application of the autologous stromal vascular fraction, an interzone of collagen fibers had formed between bone and silk-based graft. This collagen-fiber continuity partly consisted of Sharpey fibers, comparable with tendon-bone healing known for autografts and allografts. Insertion sites were more broad based at 6 months and more concentrated on the slightly protruding, bony knoblike structures at 12 months. Histologically, no differences between the treatment groups were detectable. Analysis of micro-computed tomography measurements revealed a significantly higher tissue density for the cell-seeded scaffold group as compared with the scaffold-alone group in the tibial but not femoral bone tunnel after 12 months of implantation. The novel silk fiber-based scaffold for ACL regeneration demonstrated integration into the bone tunnels via the formation of a fibrous interzone similar to allografts and autografts. Histologically, additional cell seeding did not enhance osteointegration. No significant differences between 6 and 12 months could be detected. After 12 months, there was still a considerable amount of silk present, and a longer observation period is necessary to see if a true ligament-bone enthesis will be formed

Surgical failure, mainly caused by loosening implants, causes great mental and physical trauma to patients. Improving the physicochemical properties of implants to achieve favourable osseointegration will continue to be the focus of future research. Strontium (Sr), a trace element, is often incorporated into hydroxyapatite (HA) to improve its osteogenic activity. Our previous studies have shown that miR-21 can promote the osteogenic differentiation of mesenchymal stem cells by the PI3K/β-catenin pathway. The aim of this study is to fabricate a SrHA and miR-21 composite coating and it is expected to have a favorable bone healing capability. Ti discs (20 mm diameter and one mm thickness for the in vitro section) and rods (four mm diameter and seven mm length for the in vivo section) were prepared by machining pure Ti. The Ti cylinders were placed in a Teflon-lined stainless-steel autoclave for treating at 150°C for 24 h to form SrHA layer. The miR-21 was encapsulated in nanocapsules. The miR-21 nanocapsules were mixed with CMCS powder to form a gel-like sample and uniformly coated on the SrHA modifed Ti. Osteoblast-like MG63 cells were cultured on SrHA and miR-21 modified Ti, Cell proliferation activity and osteogenesis-related gene expression were evaluated. A bone defect model was established with mature New Zealand to evaluate the osseointegration. Cylindrical holes (four mm in diameter) were created at the distal femur and tibial plateau. Each rabbit was implanted with four of the aforementioned rods (distal femur and tibial plateau of the hind legs). After implantation for one, two and three months, the rabbits were observed by X-ray and scanned using u-CT. Histological and Immunohistochemical analysis were performed to examine the osteogenic markers. A biomechanical push-in test was used to assess the bone-implant bonding strength. Both SrHA nanoparticles with good superhydrophilicity and miR-21 nanocapsules with uniform sizes were distributed evenly on the surface of the Ti. In vitro experiments revealed that the composite coating was beneficial to osteoblast proliferation, differentiation and mineralization. In vivo evaluations demonstrated that this coating could not only promote the expression of angiogenic factor CD31 but also enhance the expression of osteoblastic genes to facilitate angio-osteogenesis. In addition, the composite coating also showed a decreased RANKL expression compared with the miR-21 coating. As a result, the SrHA/miR-21 composite coating promoted new bone formation and mineralization and thus enhanced osseointegration and bone-implant bonding strength. A homogeneous SrHA and miR-21 composite coating was fabricated by generating pure Ti through a hydrothermal process, followed by adhering miR-21 nanocapsules. This coating combined the favorable physicochemical properties of SrHA and miR-21 that synergistically promoted angiogenesis, osteogenesis, osseointegration, bone mineralization and thus bone-implant bonding strength. This study provided a new strategy for surface modification of biomedical implants