Complications and results of the arthrodesis after total ankle arthroplasty failure: a retrospective monocentric study of 12 cases.

INTRODUCTION: Total ankle arthroplasty (TAA) has the objective to maintain the range of motion of the tibiotarsal joint and to preserve the nearby joints. However, the complication rate and failures remain quite high after TAA. The main objective of the study was to evaluate the improvement in the functional scores of the tibiotarsal arthrodesis after TAA failure. The secondary objective was to assess the specific complications. MATERIALS AND METHODS: This monocentric retrospective series includes 12 patients (nine men, three women, average age 52.5 years) operated between 2003 and 2018. An iliac graft was used in all cases. The arthrodesis was stabilized either by screws or by retrograde nailing. RESULTS: The reoperation was due to painful malleolar conflicts or loosening. The AOFAS score increased from 38/100 to 67/100 (51-86) post-operatively. The fusion was acquired at 3.7 months (3-6) except in two cases. DISCUSSION AND CONCLUSION: The 83% primary fusion rate is in the low average of the literature and 92% fusion rate in the high average after reoperation. All patients were improved even in two non-unions. The results of this study confirm that the arthrodesis after TAA failure is a reliable alternative to the TAA replacement. However, they are lower than those after a first-line arthrodesis.

Orthogonal and complementary measurements of properties of drug products containing nanomaterials.

Quality control of pharmaceutical and biopharmaceutical products, and verification of their safety and efficacy, depends on reliable measurements of critical quality attributes (CQAs). The task becomes particularly challenging for drug products and vaccines containing nanomaterials, where multiple complex CQAs must be identified and monitored. To reduce (i) the risk of measurement bias and (ii) the uncertainty in decision-making during product development, the combination of orthogonal and complementary analytical techniques are generally recommended by regulators. However, despite frequent reference to "orthogonal" and "complementary" in guidance documents, neither term is clearly defined. How does one determine if two analytical methods are orthogonal or complementary to one another? Definitions are needed to design a robust characterization strategy aligned to regulatory needs. Definitions for "orthogonal" and "complementary" are proposed that are compatible with existing metrological terminology and are applicable to complex measurement problems. Orthogonal methods target the quantitative evaluation of the true value of a product attribute to address unknown bias or interference. Complementary measurements include a broader scope of methods that reinforce each other to support a common decision. Examples of the application of these terms are presented, with a focus on measurement of physical properties of nano-enabled drug products, including liposomes and polymeric nanoparticles for cancer treatment, lipid-based nanoparticles (LNPs) and virus-like particles for nucleic acid delivery. The proposed framework represents a first step in advancing the assessment of the orthogonality and complementarity of two measurements and it can potentially serve as the basis for a future international standard. This framework may help product developers to implement more efficient product characterization strategies, accelerate the introduction of novel medicines to the clinic and be applicable to other therapeutics beyond nanomaterial-containing pharmaceuticals.

Improved multidetector asymmetrical-flow field-flow fractionation method for particle sizing and concentration measurements of lipid-based nanocarriers for RNA delivery.

Lipid-based nanoparticles for RNA delivery (LNP-RNA) are revolutionizing the nanomedicine field, with one approved gene therapy formulation and two approved vaccines against COVID-19, as well as multiple ongoing clinical trials. As for other innovative nanopharmaceuticals (NPhs), the advancement of robust methods to assess their quality and safety profiles-in line with regulatory needs-is critical for facilitating their development and clinical translation. Asymmetric-flow field-flow fractionation coupled to multiple online optical detectors (MD-AF4) is considered a very versatile and robust approach for the physical characterisation of nanocarriers, and has been used successfully for measuring particle size, polydispersity and physical stability of lipid-based systems, including liposomes and solid lipid nanoparticles. However, the unique core structure of LNP-RNA, composed of ionizable lipids electrostatically complexed with RNA, and the relatively labile lipid-monolayer coating, is more prone to destabilization during focusing in MD-AF4 than previously characterised nanoparticles, resulting in particle aggregation and sample loss. Hence characterisation of LNP-RNA by MD-AF4 needs significant adaptation of the methods developed for liposomes. To improve the performance of MD-AF4 applied to LNP-RNA in a systematic and comprehensive manner, we have explored the use of the frit-inlet channel where, differently from the standard AF4 channel, the particles are relaxed hydrodynamically as they are injected. The absence of a focusing step minimizes contact between the particle and the membrane, reducing artefacts (e.g. sample loss, particle aggregation). Separation in a frit-inlet channel enables satisfactory reproducibility and acceptable sample recovery in the commercially available MD-AF4 instruments. In addition to slice-by-slice measurements of particle size, MD-AF4 also allows to determine particle concentration and the particle size distribution, demonstrating enhanced versatility beyond standard sizing measurements.

Physical characterization of liposomal drug formulations using multi-detector asymmetrical-flow field flow fractionation.

Liposomal formulations for the treatment of cancer and other diseases are the most common form of nanotechnology enabled pharmaceuticals (NEPs) submitted for market approval and in clinical application today. The accurate characterization of their physical-chemical properties is a key requirement; in particular, size, size distribution, shape, and physical-chemical stability are key among properties that regulators identify as critical quality attributes. Here we develop and validate an optimized method, based on multi-detector asymmetrical-flow field flow fractionation (MD-AF4) to accurately and reproducibly separate liposomal drug formulations into their component populations and to characterize their associated size and size distribution, whether monomodal or polymodal in nature. In addition, the results show that the method is suitable to measure liposomes in the presence of serum proteins and can yield information on the shape and physical stability of the structures. The optimized MD-AF4 based method has been validated across different instrument platforms, three laboratories, and multiple drug formulations following a comprehensive analysis of factors that influence the fractionation process and subsequent physical characterization. Interlaboratory reproducibility and intra-laboratory precision were evaluated, identifying sources of bias and establishing criteria for the acceptance of results. This method meets a documented high priority need in regulatory science as applied to NEPs such as Doxil and can be adapted to the measurement of other NEP forms (such as lipid nanoparticle therapeutics) with some modifications. Overall, this method will help speed up development of NEPS, and facilitate their regulatory review, ultimately leading to faster translation of innovative concepts from the bench to the clinic. Additionally, the approach used in this work (based on international collaboration between leading non-regulatory institutions) can be replicated to address other identified gaps in the analytical characterization of various classes of NEPs. Finally, a plan exists to pursue more extended interlaboratory validation studies to advance this method to a consensus international standard.

Is amputation a viable treatment option in lower extremity trauma?

INTRODUCTION: There is currently no consensus on how to treat patients with lower extremity trauma. Should amputation be performed early on to avoid complications or should the limb be saved at any price? The goal of this study was to show that early amputation is a viable treatment option in lower extremity trauma cases. MATERIAL AND METHODS: Twenty patients who underwent early amputation and 16 patients who underwent limb-salvage were included with a minimum follow-up of 1year. The main endpoints were the Mangled Extremity Severity Score (MESS) used to predict amputation, complications, sequelae, bone union and functional outcomes. RESULTS: The amputees had a higher MESS score than those treated conservatively (7.8 vs. 4.9, P<0.00001), had a shorter hospital stay (P<0.022) and had fewer postoperative complications (P<0.003), especially infection-related (P<0.001). The prevalence of infection in limb-salvage patients was 61%. There was no significant difference between the two groups in terms of quality of life. DISCUSSION: In cases of lower extremity trauma, early amputation and limb-sparing treatment each have their advantages and disadvantages. Early amputation seems to be better in cases of complications, despite similar quality of life in the two groups in the long-term. It is a viable treatment option in cases of lower extremity trauma. Amputation must not be considered as a failure, but a deliberate choice due to the functional impact of complications that occur after limb-salvage. LEVEL OF EVIDENCE: Level IV study.