The use of injectable orthobiologics for knee osteoarthritis: A European ESSKA-ORBIT consensus. Part 1-Blood-derived products (platelet-rich plasma).

PURPOSE: The aim of this European Society of Sports Traumatology, Knee Surgery and Arthroscopy (ESSKA) consensus is to provide recommendations based on evidence and expert opinion to improve indications, decision-making and administration-related aspects when using blood-derived orthobiologics (for simplicity indicated as PRP-platelet-rich plasma-with PRP being the most common product) for the management of knee osteoarthritis (OA). METHODS: Leading European expert clinicians and scientists were divided into a steering group, a rating group and a peer review group. The steering group prepared 28 question-statement sets divided into three sections: PRP rationale and indications, PRP preparation and characterisation and PRP protocol. The quality of the statements received grades of recommendation ranging from A (high-level scientific support) to B (scientific presumption), C (low-level scientific support) or D (expert opinion). The question-statement sets were then evaluated by the rating group, and the statements scored from 1 to 9 based on their degree of agreement with the statements produced by the steering group. Once a general consensus was reached between the steering and rating groups, the document was submitted to the peer review group who evaluated the geographic adaptability and approved the document. A final combined meeting of all the members of the consensus was held to produce the official document. RESULTS: The literature review on the use of blood-derived products for knee OA revealed that 9 of 28 questions/statements had the support of high-level scientific literature, while the other 19 were supported by a medium-low scientific quality. Three of the 28 recommendations were grade A recommendations: (1) There is enough preclinical and clinical evidence to support the use of PRP in knee OA. This recommendation was considered appropriate with a strong agreement (mean: 8). (2) Clinical evidence has shown the effectiveness of PRP in patients for mild to moderate degrees of knee OA (KL ≤ 3). This recommendation was considered appropriate with a strong agreement (mean: 8.1). (3) PRP injections have been shown to provide a longer effect in comparison to the short-term effect of CS injections. They also seem to provide a safer use profile with less potential related complications. This recommendation was considered appropriate with a very strong agreement (mean: 8.7). Six statements were grade B recommendations, 7 were grade C and 12 were grade D. The mean rating score was 8.2 ± 0.3. CONCLUSIONS: The consensus group reached a high level of agreement on all the questions/statements despite the lack of clear evidence for some questions. According to the results from this consensus group, given the large body of existing literature and expert opinions, PRP was regarded as a valid treatment option for knee OA and as a possible first-line injectable treatment option for nonoperative management of knee OA, mainly for KL grades 1-3. LEVEL OF EVIDENCE: Level II.

Investigations on the Fatigue Behavior of 3D-Printed and Thermoformed Polylactic Acid Wrist-Hand Orthoses.

Additively manufactured wrist-hand orthoses (3DP-WHOs) offer several advantages over traditional splints and casts, but their development based on a patient's 3D scans currently requires advanced engineering skills, while also recording long manufacturing times as they are commonly built in a vertical position. A proposed alternative involves 3D printing the orthoses as a flat model base and then thermoforming them to fit the patient's forearm. This manufacturing approach is faster, cost-effective and allows easier integration of flexible sensors as an example. However, it is unknown whether these flat-shaped 3DP-WHOs offer similar mechanical resistance as the 3D-printed hand-shaped orthoses, with a lack of research in this area being revealed by the literature review. To evaluate the mechanical properties of 3DP-WHOs produced using the two approaches, three-point bending tests and flexural fatigue tests were conducted. The results showed that both types of orthoses had similar stiffness up to 50 N, but the vertically built orthoses failed at a maximum load of 120 N, while the thermoformed orthoses could withstand up to 300 N with no damages observed. The integrity of the thermoformed orthoses was maintained after 2000 cycles at 0.5 Hz and ±2.5 mm displacement. It was observed that the minimum force occurring during fatigue tests was approximately -95 N. After 1100-1200 cycles, it reached -110 N and remained constant. The outcomes of this study are expected to enhance the trust that hand therapists, orthopedists, and patients have in using thermoformable 3DP-WHOs.

Development of Biocomposite Alginate-Cuttlebone-Gelatin 3D Printing Inks Designed for Scaffolds with Bone Regeneration Potential.

Fabrication of three-dimensional (3D) scaffolds using natural biomaterials introduces valuable opportunities in bone tissue reconstruction and regeneration. The current study aimed at the development of paste-like 3D printing inks with an extracellular matrix-inspired formulation based on marine materials: sodium alginate (SA), cuttlebone (CB), and fish gelatin (FG). Macroporous scaffolds with microporous biocomposite filaments were obtained by 3D printing combined with post-printing crosslinking. CB fragments were used for their potential to stimulate biomineralization. Alginate enhanced CB embedding within the polymer matrix as confirmed by scanning electron microscopy (ESEM) and micro-computer tomography (micro-CT) and improved the deformation under controlled compression as revealed by micro-CT. SA addition resulted in a modulation of the bulk and surface mechanical behavior, and lead to more elongated cell morphology as imaged by confocal microscopy and ESEM after the adhesion of MC3T3-E1 preosteoblasts at 48 h. Formation of a new mineral phase was detected on the scaffold's surface after cell cultures. All the results were correlated with the scaffolds' compositions. Overall, the study reveals the potential of the marine materials-containing inks to deliver 3D scaffolds with potential for bone regeneration applications.

Development of New Hybrid Casein-Loaded PHEMA-PEGDA Hydrogels with Enhanced Mineralisation Potential.

Casein is a micellar protein rich in glutamic and aspartic acids as well as in phosphoserine. Considering its native affinity for calcium and the connection of sub-micelles through calcium phosphate nanoclusters, this protein holds promise for stimulating biomimetic mineralisation phenomena and direct binding with the mineral phase of hard tissues. In this work we prepared new hybrids based on casein embedded in a poly(2-hydroxyethyl methacrylate)-polyethyleneglycol diacrylate (PHEMA-PEGDA) hydrogel. The resulting materials were investigated structurally by Fourier transform infrared (FT-IR). Casein modified the water affinity and the rheological properties of the hybrids. The microstructure was explored by scanning electron microscopy (SEM) and the distribution of the protein was established by combined SEM micrographs and elemental mapping considering the casein-specific elements (P, N and S) not contained by the synthetic hydrogel matrix. The effect of casein on the mineralisation potential and stability of the mineral phase was investigated by FT-IR and SEM when alternating incubation in Ca/P solutions is performed. Increasing casein content in the hybrids leads to improved mineralisation, with localised formation of nanoapatite phase on the protein areas in the richest sample in protein. This behaviour was proved microstructurally by SEM and through overlapping elemental distribution of Ca and P from the newly formed mineral and P, S and N from the protein. This study indicates that nanoapatite-casein-PHEMA-PEGDA nanocomposites may be developed for potential use in bone repair and regeneration.

The Effect of Disinfectants Absorption and Medical Decontamination on the Mechanical Performance of 3D-Printed ABS Parts.

Producing parts by 3D printing based on the material extrusion process determines the formation of air gaps within layers even at full infill density, while external pores can appear between adjacent layers making prints permeable. For the 3D-printed medical devices, this open porosity leads to the infiltration of disinfectant solutions and body fluids, which might pose safety issues. In this context, this research purpose is threefold. It investigates which 3D printing parameter settings are able to block or reduce permeation, and it experimentally analyzes if the disinfectants and the medical decontamination procedure degrade the mechanical properties of 3D-printed parts. Then, it studies acetone surface treatment as a solution to avoid disinfectants infiltration. The absorption tests results indicate the necessity of applying post-processing operations for the reusable 3D-printed medical devices as no manufacturing settings can ensure enough protection against fluid intake. However, some parameter settings were proven to enhance the sealing, in this sense the layer thickness being the most important factor. The experimental outcomes also show a decrease in the mechanical performance of 3D-printed ABS (acrylonitrile butadiene styrene) instruments treated by acetone cold vapors and then medical decontaminated (disinfected, cleaned, and sterilized by hydrogen peroxide gas plasma sterilization) in comparison to the control prints. These results should be acknowledged when designing and 3D printing medical instruments.

DICOM 3D viewers, virtual reality or 3D printing - a pilot usability study for assessing the preference of orthopedic surgeons.

As standard practice in orthopedic surgery, the information gathered by analyzing Computer Tomography (CT) 2D images is used for patient diagnosis and planning surgery. Lately, these virtual slices are the input for generating 3D virtual models using DICOM viewers, facilitating spatial orientation, and diagnosis. Virtual Reality (VR) and 3D printing (3DP) technologies are also reported for use in anatomy visualization, medical training, and diagnosis. However, it has not been yet investigated whether the surgeons consider that the advantages offered by 3DP and VR outweigh their development efforts. Moreover, no comparative evaluation for understanding surgeon's preference in using these investigation tools has been performed so far. Therefore, in this paper, a pilot usability test was conducted for collecting surgeons' opinions. 3D models of knee, hip and foot were displayed using DICOM 3D viewer, two VR environments and as 3D-printed replicas. These tools adequacy for diagnosis was comparatively assessed in three cases scenarios, the time for completing the diagnosis tasks was recorded and questionnaires filled in. The time for preparing the models for VR and 3DP, the resources needed and the associated costs were presented in order to provide surgeons with the whole context. Results showed a preference in using desktop DICOM viewer with 3D capabilities along with the information provided by Unity-based VR solution for visualizing the virtual model from various angles challenging to analyze on the computer screen. 3D-printed replicas were considered more useful for physically simulating the surgery than for diagnosis. For the VR and 3DP models, the lack of information on bone quality was considered an important drawback. The following order of using the tools was preferred: DICOM viewer, followed by Unity VR and 3DP.

Development of 3D Bioactive Scaffolds through 3D Printing Using Wollastonite-Gelatin Inks.

The bioactivity of scaffolds represents a key property to facilitate the bone repair after orthopedic trauma. This study reports the development of biomimetic paste-type inks based on wollastonite (CS) and fish gelatin (FG) in a mass ratio similar to natural bone, as an appealing strategy to promote the mineralization during scaffold incubation in simulated body fluid (SBF). High-resolution 3D scaffolds were fabricated through 3D printing, and the homogeneous distribution of CS in the protein matrix was revealed by scanning electron microscopy/energy-dispersive X-ray diffraction analysis (SEM/EDX) micrographs. The bioactivity of the scaffold was suggested by an outstanding mineralization capacity revealed by the apatite layers deposited on the scaffold surface after immersion in SBF. The biocompatibility was demonstrated by cell proliferation established by MTT assay and fluorescence microscopy images and confirmed by SEM micrographs illustrating cell spreading. This work highlights the potential of the bicomponent inks to fabricate 3D bioactive scaffolds and predicts the osteogenic properties for bone regeneration applications.

A Review on 3D-Printed Templates for Precontouring Fixation Plates in Orthopedic Surgery.

This paper is a systematic review of the literature on 3D-printed anatomical replicas used as templates for precontouring the fixation plates in orthopedic surgery. Embase, PubMed, Cochrane, Scopus and Springer databases were consulted for information on design study, fracture anatomical location, number of patients, surgical technique, virtual modeling approach and 3D printing process. The initial search provided a total of 496 records. After removing the duplicates, the title and abstract screening, and applying exclusion criteria and citations searching, 30 papers were declared eligible and included in the final synthesis. Seven studies were identified as focusing on retrospective non-randomized series of clinical cases, while two papers presented randomized case control studies. Two main approaches were highlighted in developing 3D-printed anatomical models for precontouring fixation plates: (a.) medical reconstruction, virtual planning and fracture reduction followed by 3D printing the model; (b.) medical reconstruction followed by 3D printing the model of the mirrored uninjured side. Revised studies reported advantages such as surgical time and blood loss reduction, while the reduction quality is similar with that of the conventional surgery. During the last couple of years there was an increase in the number of studies focused on precontouring orthopedic plates using 3D printing technology. Three-dimensionally-printed templates for plate precontouring were mostly used for acetabular fractures. Knowledge on medical virtual modeling and reconstruction is mandatory.

Clavicle anatomical osteosynthesis plate breakage - failure analysis report based on patient morphological parameters.

Clavicle fracture reported incidence is about 5% of fractures in adult; among them, those located in the middle third of the shaft represent more than 80% from the total of cases. Due to the special morphological and biomechanical constraints of the clavicle, several methods for restoring morphological integrity in these fractures are described, including conservative, non-surgical treatment. The last 10 years of clinical studies in the field have favored the surgical treatment for selected cases; several osteosynthesis implants are in use - mostly anatomical plates with specific advantages and documented complications. A failed anatomical clavicle plate was explanted and analyzed after a protocol using stereomicroscopy, scanning electron microscopy and energy dispersive spectrometry. Based on the computed tomography (CT) scan determination of patient morphological parameters, a finite elements analysis of the failure scenario was completed. The failure analysis has proved that the plate breakage had occurred in the point of maximal elastic stress and minor deformation. The clinical implication is that no hole should remain free of screw during clavicle plate fixation and the implant should be chosen based on patient morphological parameters. In comminuted clavicle fracture, anatomic bridging with locked plate technique may lead to implant failure due to increase of the stress in the midshaft area. Thorough knowledge of anatomy and morphology of complex bones like the clavicle is necessary. Modern osteosynthesis anatomical implants are still to be improved.

A late and difficult diagnosis of ochronosis.

Alkaptonuria is a rare autosomal recessive disorder of metabolism caused by deficiency of homogentisic acid oxidase and resulting in accumulation of homogentisic acid in collagenous structures. This causes the classic clinical triad: (1) homogentisic aciduria (urine blackens on standing when oxidized or alkalinized); (2) eumelanin-like pigmentation of skin, sclera, cartilages, etc and (3) degenerative ochronic arthropathies usually in the fourth decade of life. Other important but more rare consequences of alkaptonuric ochronosis are cardiovascular and urinary tract involvement. We present a case of ochronosis with multiple visceral involvement: skin (fingers, ear sclera), severe spondylarthropaty with extensive calcifications of intervertebral discs and reduced mobility, osteoarthritis of both knees, right hip ostonecrosis, cardiovascular involvement (severe stenosis and insufficiency of aortic valve that) and urinary tract involvement (nephrolitiasis)

Outside-in meniscus suture technique: 5 years' follow-up.

We present the results of a prospective study evaluating the arthroscopic technique of outside-in meniscus suture (n=68). The types of tears suitable for suture consisted of acute vertical tears, solitary or in association with a radial tear in middle third. The technique was always outside-in using resorbable sutures (2-0 PDS, 2-0 Maxon). Follow-up evaluation included clinical examination, radiographic examinations and second-look arthroscopies (n=10). There were four failures in this study, consisting of rerupture of the meniscus. Clinical results were good in 91% with complete recovery and return to physical and sportive activity, good in 3% with mild symptoms, and failure in 6% consisting of meniscus rerupture.

Streptokinase and enoxaparin in the pre-hospital management of the ST-segment elevation acute myocardial infarction.

UNLABELLED: In a pilot study, safety and efficacy of an accelerated Streptokinase (SK) regimen (0.75 MU/10 min. repeated after 50 min. if no signs of coronary reperfusion were detected) in combination with enoxaparin was evaluated in the prehospital (preASENOX regimen) and in the in-hospital (in ASENOX regimen) phase of the ST segment elevation acute myocardial infarction (STAMI) and compared to the in-hospital standard SK plus Heparin (the StSK regimen). METHODS: A group of 262 consecutive patients (age 34-74 years) thrombolised within the first 6 hours after the onset of STAMI was divided in three subgroups according to the mentioned regimens: preASENOX (64 patients); in ASENOX (69 patients) and StSK (129 patients). Enoxaparin was administered i.v. 40 mg before the first dose of 0.75 MU of SK and 1 mg/kg every 12 hours for 5-7 days. Heparin was infused 1000 i.u./h 48-96 hrs. Three noninvasive reperfusion criteria were used: 1) Rapid cessation of the chest pain; 2) Rapid decreasing of the ST segment elevations by more than 50% from the initial value; 3) Rapid increasing of the CK and CK-MB with a peak within the first 12 hrs. RESULTS: The chest pain-thrombolysis time was 145 +/- 52 min in the preASENOX subgroup, significantly shorter as that in the ASENOX subgroup (172 +/- 73 min, p = 0.016) and the StSK one (168 +/- 80 min, p = 0.038). The ratios of the CR were 81.2%, 78.2% and 62.0%, respectively (preASENOX vs StSK p = 0.025; in ASENOX vs StSK p = 0.030). The inhospital mortalities were: 3.12% (preASENOX); 5.8% (inASENOX) and 10.8% (StSK)(non-significant differences). Only one case of ischemic stroke was registered (in the inASENOX subgroup). Symptomatic hypotension appeared more frequent in the preASENOX (39.06%), and inASENOX (43.47%) subgroups as compared to the SSK one (20.15%). CONCLUSIONS: 1) The preASENOX and inASENOX regimens are safe, and lead toward a significant higher ratios of coronary reperfusion as compared to StSK regimen; 2) Our data suggest a very low mortality in patients treated with the preASENOX regimen. Further investigations (randomized studies) are needed for a definite conclusion.