A multivariate formulation and process development platform for direct compression.

The efficient development of robust tableting processes is challenging due to the lack of mechanistic understanding on the impact of raw material properties and process parameters on tablet quality. The experimental determination of the effect of process and formulation parameters on tablet properties and subsequent optimization is labor-intensive, expensive and time-consuming. The combined use of an extensive raw material property database, process simulation tools and multivariate modeling allows more efficient and more optimized development of the direct compression (DC) process. In this study, key material attributes and in-process mechanical properties with a potential effect on tablet processability and tablet properties were identified. In a first step, an extensive characterization of 55 raw materials (over 100 material descriptors) (Van Snick et al., 2018) and 26 formulation blends (31 material descriptors) (Dhondt et al., 2022) was performed. These blends were subsequently compacted on a compaction simulator under multiple process conditions through a design of experiments (DoE) approach. A T-shaped partial least squares (T-PLS) model was established which correlates tablet quality attributes with process settings, raw material properties and blend ratios. During future development of the DC formulation and process for a new active pharmaceutical ingredient (API), this model can then be used to provide a preliminary formulation and compaction process settings as starting point to be further optimized during development trials based on well-defined raw material characteristics and compaction tests. This study hence contributes to a better understanding on the impact of raw material properties and process settings on a DC process and final properties of the produced tablets; and provides a platform allowing a more efficient and more optimized development of a robust tableting process.

Equal bony resection of distal and posterior femur will lead to flexion/extension gap inequality in robot-assisted cruciate-retaining TKA.

PURPOSE: Joint imbalance has become one of the main reasons for early revision after total knee arthroplasty (TKA) and it is directly related to the surgical technique. Therefore, a better understanding of how much bone has to be removed to obtain a balanced flexion/extension gap could improve current practice. The primary objective of this study was to analyse the amount of bone that needed to be removed from the distal and posterior femoral joint surfaces to obtain an equal flexion/extension gap in robot-assisted TKA. The second objective of this study was to evaluate whether the size of the knee joint influenced the amount of bony resection needed to achieve an equal flexion/extension gap in robot-assisted TKA. METHODS: A retrospective analysis was performed on all patients receiving a robot-assisted TKA (Cruciate Retaining (n = 268)) by six surgeons from April 2018 to September 2019. The robot was used consecutively when available in all patients receiving Cruciate Retaining TKA. Gap assessment, bony resections, femoral implant size and hip-knee-ankle angle were evaluated with the robot. Femoral implant size was categorized into small (size 1-2), medium (size 3-5) and large (size 6-8). RESULTS: The difference between the posterior and distal resection needed to obtain equal flexion and extension gap was on average 2.0 mm (SD 1.6) and 1.5 mm (SD 2.2) for the medial and lateral compartment, respectively. The discrepancy was smaller in the large implant group compared to the small implant group (p < .05 medial and lateral) and medium implant group (p < .05 medial). Varus knees required a larger differential resection compared to neutral and valgus knees (only laterally) (medial compartment: p < .05 (varus-neutral), p = .051 (varus-valgus); lateral compartment: p < .05 (varus-neutral and varus-valgus). CONCLUSION: Removing an equal amount of bone from the distal and posterior femur will lead to flexion/extension gap imbalance in TKA. It was required to remove 1.5-2 mm more bone from the posterior femur compared to the distal femur to equalize flexion and extension gap. This effect was size dependent: in larger knees, the discrepancy between the distal and posterior resections was smaller. LEVEL OF EVIDENCE: IV.

Robot-assisted total knee arthroplasty is associated with a learning curve for surgical time but not for component alignment, limb alignment and gap balancing.

PURPOSE: The application of robotics in the operating theatre for total knee arthroplasty (TKA) remains controversial. As with all new technology, the introduction of new systems is associated with a learning curve and potentially associated with extra complications. Therefore, the aim of this study is to identify and predict the learning curve of robot-assisted (RA) TKA. METHODS: A RA TKA system (MAKO) was introduced in April 2018 in our service. A retrospective analysis was performed of all patients receiving a TKA with this system by six surgeons. Operative times, implant and limb alignment, intraoperative joint balance and robot-related complications were evaluated. Cumulative summation (CUSUM) analyses were used to assess learning curves for operative time, implant alignment and joint balance in RA TKA. Linear regression was performed to predict the learning curve of each surgeon. RESULTS: RA TKA was associated with a learning curve of 11-43 cases for operative time (p < 0.001). This learning curve was significantly affected by the surgical profile (high vs. medium vs. low volume). A complete normalisation of operative times was seen in four out of five surgeons. The precision of implant positioning and gap balancing showed no learning curve. An average deviation of 0.2° (SD 1.4), 0.7° (SD 1.1), 1.2 (SD 2.1), 0.2° (SD 2.9) and 0.3 (SD 2.4) for the mLDFA, MPTA, HKA, PDFA and PPTA from the preoperative plan was observed. Limb alignment showed a mean deviation of 1.2° (SD 2.1) towards valgus postoperatively compared to the intraoperative plan. One tibial stress fracture was seen as a complication due to suboptimal positioning of the registration pins. CONCLUSION: RA TKA is associated with a learning curve for surgical time, which might be longer than reported in current literature and dependent on the profile of the surgeon. There is no learning curve for component alignment, limb alignment and gap balancing. LEVEL OF EVIDENCE: IV.

The Influence of Equipment Design and Process Parameters on Granule Breakage in a Semi-Continuous Fluid Bed Dryer after Continuous Twin-Screw Wet Granulation.

The drying unit of a continuous from-powder-to-tablet manufacturing line based on twin-screw granulation (TSG) is a crucial intermediate process step to achieve the desired tablet quality. Understanding the size reduction of pharmaceutical granules before, during, and after the fluid bed drying process is, however, still lacking. A first major goal was to investigate the breakage and attrition phenomena during transport of wet and dry granules, the filling phase, and drying phase on a ConsiGma-25 system (C25). Pneumatic transport of the wet granules after TSG towards the dryer induced extensive breakage, whereas the turbulent filling and drying phase of the drying cells caused rather moderate breakage and attrition. Subsequently, the dry transfer line was responsible for additional extensive breakage and attrition. The second major goal was to compare the influence of drying air temperature and drying time on granule size and moisture content for granules processed with a commercial-scale ConsiGma-25 system and with the R&D-scale ConsiGma-1 (C1) system. Generally, the granule quality obtained after drying with C1 was not predictive for the C25, making it challenging during process development with the C1 to obtain representative granules for the C25.

Reduced joint awareness after total knee arthroplasty with a cruciate retaining design.

A range of different total knee arthroplasty (TKA) designs have been developed, each specifically designed to relieve pain and restore knee function with the greatest possible patient satisfaction. The purpose of this study was to compare a posterior stabilized design and a cruciate-retaining design. We hypothesized that a cruciate-retaining design would have a higher Forgotten Joint Score (FJS) than a posterior stabilized design. Ninety-two patients were used in our analysis (46 patients in each group) involving TKA (Attune, Depuy-Synthes) between January 2014 and March 2015. We excluded patients with valgus alignment, post-traumatic arthritis, rheumatoid arthritis and major previous surgery on the knee. We compared the FJS, the Oxford Knee Score (OKS) and their ceiling effects. FJS was significantly higher in the fixed-bearing cruciate-retaining group (P=0.043). The mean (-SD) FJS for the cruciate-retaining group was 78,4-25.1 compared to 67.6-27.6 for the posterior stabilized group. No significant difference in OKS was detected. The total ceiling effect for FJS and OKS was 32.2% and 45.5%, respectively. In conclusion, patients with cruciate-retaining TKA showed a better FJS in comparison to posterior stabilized TKA. FJS has a higher discriminatory power compared to OKS.

Heat Transfer Evaluation During Twin-Screw Wet Granulation in View of Detailed Process Understanding.

During the last decade, the pharmaceutical industry has shown a growing interest in continuous twin-screw granulation (TSG). Despite flourishing literature on TSG, limited studies focused on fundamental process understanding on its mechanisms. In current study, granule quality attributes along the length of the TSG barrel were evaluated together with heat transfer in order to achieve a more fundamental understanding of the granulation process. An experimental setup was developed allowing the collection of granules at the different TSG compartments. In addition to the determination of typical granule attributes, mechanical energy, barrel and granule temperature (measured using an in-line implemented infra-red camera) were measured to evaluate heat transfer occurring at the different compartments and to relate them to granulation mechanisms. Collected data identified wetting enthalpy and friction forces as the main sources of heat along the granulator length. Wetting occurred in the wetting zone and generated temperature increase depending on liquid-to-solid ratio and powder wettability. In the kneading zones, granule temperature increase was proportional to mechanical energy. While it is usually admitted that granule consolidation and reshaping are the consequence of the high shear experienced by the granules, it was highlighted that most of the mechanical energy is converted into thermal energy with no correlation between mechanical energy and granule size distribution. Combined mass and energy balance of the granulation process are therefore necessary to capture the interaction between granule properties and physico-chemical and mechanical phenomena occurring in each compartment.

Medial Unicompartmental Knee Arthroplasty with a Fixed Bearing Implant.

Unicompartmental knee arthroplasty (UKA) is an alternative to total knee arthroplasty in isolated medial arthritis. UKA restores native tibial and femoral joint surfaces and corrects pre-disease limb alignment, by which natural knee biomechanics are restored, ensuring effective functional recovery. Proper patient selection and accurate surgical technique contribute to good functional outcome and long-term survival. The key steps of the procedure (as well as multiple tips and tricks) are demonstrated in the video article: (1) preoperative assessment and planning; (2) patient positioning and setup; (3) exposure; (4) instrument options and surgical technique; (5) distal femoral resection; (6) proximal tibial resection; (7) assessment of alignment and gaps; (8) finishing the femur-sizing, position, and posterior resection; (9) finishing the tibia-sizing and position; (10) trialing the implant; (11) implanting final components-cementing technique; (12) closure; and (13) rehabilitation. Following these surgical steps and principles will lead to excellent functional long-term results with a low revision rate and a minimum of complications.

Outcomes of a Fixed-Bearing, Medial, Cemented Unicondylar Knee Arthroplasty Design: Survival Analysis and Functional Score of 460 Cases.

BACKGROUND: Unicompartmental knee arthroplasty (UKA) is an alternative to total knee arthroplasty in isolated medial osteoarthritis (OA). However, despite satisfactory reports on the clinical performance, UKA revision rates are still concerning. This retrospective study reports on the long-term survivorship, functional outcomes, and reasons for revision in fixed-bearing UKA implant. METHODS: Between 2005 and 2013, 460 consecutive patients were treated with medial UKA in one center using a fixed-bearing UKA system. All patients were evaluated clinically and radiographically before surgery, and postoperatively at 6 weeks and 1 year. Between February and April 2016, all patients were reevaluated using the Oxford Knee Score. RESULTS: Mean follow-up was 5.5 (range, 2-11) years. The mean Oxford Knee Score was 43.3 (7-48), with 94.6% patients showing excellent or good outcomes. Eleven revisions (2.4%) occurred. The survivorship was 97.2% (95% confidence interval, 96.2%-99.2%) and 94.2% (95% confidence interval, 86.8%-97.5%) at 5 and 10 years, respectively, with revision of any implant component for any reason as the end point. The causes for revision were infection (4 cases, 0.9%); lateral pain due to overload (2 cases, 0.4%); progression of OA in the lateral compartment (2 cases, 0.4%); patellar pain with patellar chondropathy (2 cases, 0.4%); and severe synovitis (1 cases, 0.2%). There were no reoperations or revisions for component loosening, instability, component wear, or periprosthetic fracture. CONCLUSION: A fixed-bearing UKA system is a good treatment option for medial end-stage OA. Satisfactory functional results were achieved with low incidence of complications and revisions.

Traumatic proximal tibiofibular dislocation.

Traumatic proximal tibiofibular dislocation is a rare injury that is often unrecognized or misdiagnosed at the initial presentation because of a lack of clinical suspicion. When diagnosed, the injury should be promptly reduced. Missed injuries or late presentations are a potential source of chronic morbidity. This article describes the relevant anatomy, classifications, and diagnostic and therapeutic approaches. The authors stress the importance of evaluating the distal syndesmotic ligaments and the interosseous membrane because the mechanism of trauma can also cause a disruption of the distal tibiofibular syndesmosis. In the presence of syndesmotic instability, prompt stabilization is advocated. Whether syndesmotic stabilization is indicated in cases of a syndesmotic sprain is controversial. An illustrative case is also presented of a 28-year-old male soccer player who sustained a proximal tibiofibular dislocation after a violent twisting motion of the right knee.