Low back pain (LBP) is the main cause of disability worldwide and is primarily triggered by intervertebral disc degeneration (IDD). Although several treatment options exist, no therapeutic tool has demonstrated to halt the progressive course of IDD. Therefore, several clinical trials are being conducted to investigate different strategies to regenerate the intervertebral disc, with numerous studies not reaching completion nor being published. The aim of this study was to analyze the publication status of clinical trials on novel regenerative treatments for IDD by funding source and identify critical obstacles preventing their conclusion. Prospective clinical trials investigating regenerative treatments for IDD and registered on . ClinicalTrials.gov. were included. Primary outcomes were publication status and investigational treatment funding. Fisher's exact test was utilized to test the association for categorical variables between groups. 25 clinical trials were identified. Among these, only 6 (24%) have been published. The most common source of funding was university (52%), followed by industry (36%) and private companies (12%). Investigational treatments included autologous (56%) or allogeneic (12%) products alone or in combination with a carrier or delivery system (32%). The latter were more likely utilized in industry or privately funded studies (Fig. 1, p=0.0112). No significant difference was found in terms of funding regarding the publication status of included trials (Table 1, p=0.9104). Most clinical trials investigating regenerative approaches for the treatment of IDD were never completed nor published. This is likely due to multiple factors, including difficult enrollment, high dropout rate, and publication bias. 3. More accurate design and technical support from stakeholders and clinical research organization (CROs) may likely increase the quality of future clinical trials in the field. For any figures or tables, please contact the authors directly

Fracture nonunion is a severe clinical problem for the patient, as well as for the clinician. About 5-20% of fractures does not heal properly after more than six months, with a 19% nonunion rate for tibia, 12% for femur and 13% for humerus, leading to patient morbidity, prolonged hospitalization, and high costs. The standard treatment with iliac crest-derived autologous bone filling the nonunion site may cause pain or hematoma to the patient, as well as major complications such as infection. The application of mesenchymal autologous cells (MSC) to improve bone formation calls for randomized, open, two-arm clinical studies to verify safety and efficacy. The ORTHOUNION * project (ORTHOpedic randomized clinical trial with expanded bone marrow MSC and bioceramics versus autograft in long bone nonUNIONs) is a multicentric, open, randomized, comparative phase II clinical trial, approved in the framework of the H2020 funding programme, under the coordination of Enrique Gòmez Barrena of the Hospital La Paz (Madrid, Spain). Starting from January 2017, patients with nonunion of femur, tibia or humerus have been actively enrolled in Spain, France, Germany, and Italy. The study protocol encompasses two experimental arms, i.e., autologous bone marrow-derived mesenchymal cells after expansion (‘high dose’ or ‘low dose’ MSC) combined to ceramic granules (MBCP™, Biomatlante), and iliac crest-derived autologous trabecular bone (ICAG) as active comparator arm, with a 2-year follow-up after surgery. Despite the COVID 19 pandemic with several lockdown periods in the four countries, the trial was continued, leading to 42 patients treated out of 51 included, with 11 receiving the bone graft (G1 arm), 15 the ‘high dose’ MSC (200x10. 6. , G2a arm) and 16 the ‘low dose’ MSC (100x10. 6. , G2b arm). The Rizzoli Orthopaedic Institute has functioned as coordinator of the Italian clinical centres (Bologna, Milano, Brescia) and the Biomedical Science and Technologies and Nanobiotechnology Lab of the RIT Dept. has enrolled six patients with the collaboration of the Rizzoli’ 3rd Orthopaedic and Traumatological Clinic prevalently Oncologic. Moreover, the IOR Lab has collected and analysed the blood samples from all the patients treated to monitor the changes of the bone turnover markers following the surgical treatment with G1, G2a or G2b protocols. The clinical and biochemical results of the study, still under evaluation, are presented. * ORTHOUNION Horizon 2020 GA 733288

Device-associated bacterial infections are a major and costly clinical challenge. This project aimed to develop a smart new biomaterial for implants that helps to protect against infection and inflammation, promote bone growth, and is biodegradable. Gallium (Ga) doped strontium-phosphate was coated on pure Magnesium (Mg) through a chemical conversion process. Mg was distributed in a graduated manner throughout the strontium-phosphate coating GaSrPO4, with a compact structure and a Ga-rich surface. We tested this sample for its biocompatibility, effects on bone remodeling and antibacterial activities including Staphylococcus aureus, S. epidermidis and E. coli - key strains causing infection and early failure of the surgical implantations in orthopaedics and trauma. Ga was distributed in a gradient way throughout the entire strontium-phosphate coating with a compact structure and a gallium-rich surface. The GaSrPO4 coating protected the underlying Mg from substantial degradation in minimal essential media at physiological conditions over 9 days. The liberated Ga ions from the coatings upon Mg specimens inhibited the growth of bacterial tested. The Ga dopants showed minimal interferences with the SrPO4 based coating, which boosted osteoblasts and undermined osteoclasts in in vitro co-cultures model. The results evidenced this new material may be further translated to preclinical trial in large animal model and towards clinical trial. Acknowledgements: Authors are grateful to the financial support from the Australian Research Council through the Linkage Scheme (ARC LP150100343). The authors acknowledge the facilities, and the scientific and technical assistance of the RMIT University and John Curtin School of Medical Research, Australian National University

The World Health Organisation (WHO) has included low back pain in its list of twelve priority diseases. Notably, Degenerative disc disease (DDD) presents a large, unmet medical need which results in a disabling loss of mechanical function. Today, no efficient therapy is available. Chronic cases often receive surgery, which may lead to biomechanical problems and accelerated degeneration of adjacent segments. Our consortium partners have developed and studied mesenchymal stem cell-based, regenerative therapies trials. In previous phase 2 trial, patients exhibited rapid and progressive improvement of functional and pain indexes after 1 year with no significant side effects. To develop the world's first rigorously proven, effective treatment of DDD, EUROSPINE aims to assess, via a multicentre, randomized, controlled, phase 2b clinical trial including 112 patients with DDD, the efficacy of an allogenic intervertebral mesenchymal stem cell (MSC)-based therapy. This innovative therapy aims to rapidly and sustainably (at least 24 months) reduce pain and disability. In addition, the consortium aims to provide new knowledge on immune response & safety associated with allogeneic BM-MSC intradiscal injection. This simple procedure would be cost-effective, minimally invasive, and standardised. At the end of the RESPINE trial, we aim to propose a broadly available and clinically applicable treatment for DDD, marketed by European SMEs

Study aim. There is an ever increasing demand for quality clinical trials in surgery. Surgeons' co-operation and enthusiasm to participate are important, if not crucial in success of such studies, especially if they are multi-centred. Clinician's individual uncertainty (equipoise) about a case has been often cited as an ethical basis for inviting a patient to take part in a clinical trial. This study aims to establish current attitudes of surgeons participating in a national multi-centred randomised controlled trial and explores an on line tool for instant assessment of collective uncertainty (equipoise) for individual clinical cases eligible for a trial. Study design. Surgeons taking part in the UK Heel Fracture Trial were invited to take part. If agreed, they were asked to evaluate treatment prognosis for eligible for the trial anonymised cases of calcaneal fractures online by means of specially designed system. The cases were published on a password protected website on ad-hoc basis during the three years course of the trial. Their responses were submitted instantly on line. Results. 16 out of 24 surgeons agreed to participate. The participating surgeons were emailed links to cases (normally in butches of three) less than once a month. It took them 10-15 min to assess all three cases via interactive interface. Of those who agreed 12 submitted their opinion at least once. 7 voted consistently during the course of the trial. Seventy one cases had been published. The data collected from responses allowed to assess individual and collective uncertainty about clinical cases. 4 surgeons demonstrated tendency towards individual uncertainty, balanced by 4 who did not accept it. However, sufficient collective uncertainty was demonstrated in 84.5% of cases. Discussion. Level of surgeons' enthusiasm towards clinical research appears to be moderate in a selected population of orthopaedic surgeons who already agreed to take part in a randomised clinical trial, despite a very low research time burden of this study. It is important to continue to promote multi-centred studies in order to improve surgeons' attitude towards quality clinical research. Extra efforts by academic clinicians to develop further low research time burden methodologies may increase acceptance and volume of multi-centred clinical research. This study supports previously expressed view that individual uncertainty is a very unreliable and unnecessary justification to offer a subject to take part in a clinical trial. The system used in the study offers surgeons to express their opinions and preferences freely. The instant on line comparison of opinions provides a clear assessment of collective uncertainty, which can be returned to a treating surgeon and a patient him/herself within 48 hours. In absence of collective uncertainty it would be ethical to offer a patient the best treatment according to current opinion. These cases can then be followed up as part of an inclusive trial, if a subject agrees. We believe that using the system may improve decision making process in randomised controlled trials, for example in selected challenging cases

Background. Definitive proof is lacking on mesenchymal stem cell (MSCs) cellular therapy to regenerate bone if biological potential is insufficient. High number of MSCs after GMP expansion may solve the progenitor insufficiency at the injury but clinical trials are pending. Methods. A prospective, multicenter, multinational Phase I/IIa interventional clinical trial was designed under the EU-FP7 REBORNE Project to evaluate safety and early efficacy of autologous expanded MSCs loaded on biomaterial at the fracture site in diaphyseal and/or metaphysodiaphyseal fractures (femur, tibia, humerus) nonunions. The trial included 30 recruited patients among 5 European centres in France, Spain, Germany, and Italy. Safety endpoints (local and general complication rate) and secondary endpoints for early efficacy (number of patients with clinically and radiologically proven bone healing at 12 and 24 weeks) were established. Cultured MSCs from autologous bone marrow, expanded under GMP protocol was the Investigational Medicinal Product, standardised in the participating countries confirming equivalent cell production in all the contributing GMP facilities. Cells were mixed with CE-marked biphasic calcium phosphate biomaterial in the surgical setting, at an implanted dose of 20−106 cells per cc of biomaterial (total 10cc per case) in a single administration, after debridement of the nonunion. Results. Of 30 recruited patients, 28 patients received the treatment and completed the protocol up to 24 weeks (one case pending at submission). No adverse effects related to cells were detected. Two superficial infections associated to musculoskeletal flaps were solved with antibiotics. Preliminary efficacy results at 3 months confirmed 14 consolidations (out of 27 cases, 52%). At 6 months, 20 consolidations (out of 26 cases, 77%) were confirmed. One failure underwent reoperation at 6 months. One case FU was pending at submission. Conclusions. Preliminary results confirm safety, feasibility and efficacy at 3 and 6 months with the described procedure. Level of evidence. II

Our knowledge of primary bone marrow edema (BME) of the knee is still limited. A major contributing factor is that it shares several radiological findings with a number of vascular, traumatic, and inflammatory conditions having different histopathological features and etiologies.

BME can be primary or secondary. The most commonly associated conditions are osteonecrosis, osteochondritis dissecans, complex regional pain syndrome, mechanical strain such as bone contusion/bruising, micro-fracture, stress fracture, osteoarthritis, and tumor. The etiology and pathogenesis of primary BME are unclear. Conservative treatment includes analgesics, non-steroidal anti-inflammatory drugs, weight-bearing limitations, physiotherapy, pulsed electromagnetic fields, prostacyclin, and bisphosphonates. Surgical treatment, with simple perforation, fragment stabilization, combined scraping and perforation, and eventually osteochondral or chondrocyte transplant, is reserved for the late stages. This retrospective study of a cohort of patients with primary BME of the knee was undertaken to describe their clinical and demographic characteristics, identify possible risk factors, and assess treatment outcomes.

We reviewed the records of 48 patients with primary BME of the knee diagnosed on MRI by two radiologists and two orthopedists. History, medications, pain type, leisure activities, smoking habits, allergies, and environmental factors were examined. Analysis of patients’ characteristics highlighted that slightly overweight middle-aged female smokers with a sedentary lifestyle are the typical patients with primary BME of the knee. In all patients, the chief symptom was intractable day and night pain (mean value, 8.5/10 on the numerical rating scale) with active as well as passive movement, regardless of BME extent. Half of the patients suffered from thyroid disorders; indeed, the probability of having a thyroid disorder was higher in our patients than in two unselected groups of patients, one referred to our orthopedic center (odds ratio, 18.5) and another suffering from no knee conditions (odds ratio, 9.8). Before pain onset, 56.3% of our cohort had experienced a stressful event (mourning, dismissal from work, concern related to the COVID-19 pandemic). After conservative treatment, despite the clinical improvement and edema resolution on MRI, 93.8% of patients described two new symptoms: a burning sensation in the region of the former edema and a reduced ipsilateral patellar reflex. These data suggest that even though the primary BME did resolve on MRI, the knee did not achieve full healing.

Total knee replacement (TKR) design aims to restore normal kinematics with emphasis on flexion range. The survivorship of a TKR is dependent on the kinematics in six-degrees-of-freedom (6-DoF). Stepping up, such as stair ascent is a kinematically demanding activity after TKR. The debate about design choice has not yet been informed by 6-DoF in vivo kinematics. This prospective randomised controlled trial (RCT) compared kneeling kinematics in three TKR designs.

68 participants were randomised to receive either cruciate retaining (CR-FB), rotating platform (CR-RP) or posterior stabilised (PS-FB) prostheses. Image quality was sufficient for 49 of these patients to be included in the final analysis following a minimum 1-year follow-up. Patients completed a step-up task while being imaged using single-plane fluoroscopy. Femoral and tibial computer-aided design (CAD) models for each of the TKR designs were registered to the fluoroscopic images using bespoke software OrthoVis to generate six-degree-of-freedom kinematics. Differences in kinematics between designs were compared as a function of flexion.

There were no differences in terminal extension between the groups. The CR-FB was further posterior and the CR-RP was more externally rotated at terminal extension compared to the other designs. Furthermore, the CR-FB designs was more posteriorly positioned at each flexion angle compared to both other designs. Additionally, the CR-RP design had more external femoral rotation throughout flexion when compared with both fixed bearing designs. However, there were no differences in total rotation for either step-up or down. Visually, it appears there was substantial variability between participants in each group, indicating unique patient-specific movement patterns.

While use of a specific implant design does influence some kinematic parameters, the overall patterns are similar. Furthermore, there is high variability indicating patient-specific kinematic patterns. At a group level, none of these designs appear to provide markedly different step-up kinematic patterns. This is important for patient expectations following surgery. Future work should aim to better understand the unique patient variability.

BACKGROUND. Diffuse noxious inhibitory control (DNIC) is impaired in people with chronic pain such as knee osteoarthritis (KOA), which may predict the risk of acute-to-chronic pain transition. Electroacupuncture (EA) is effective in relieving pain in patients with KOA. However, whether EA may inhibit acute-to-chronic pain transition of KOA has not been systematically examined. METHODS. This was a multicenter, three-arm parallel, single-blind randomized controlled trial involving a total of 450 patients with KOA. This study was approved by the Chinese Ethics Committee of Registering Clinical Trials (reference: ChiECRCT-20140035) and registered with Chinese Clinical Trial Registry (ChiCTR-ICR-14005411). Patients were divided into three groups based on EA current intensity: strong EA (>2mA), weak EA (<0.5mA) and sham EA (none acupoint). Treatments consisted of five sessions per week, for two weeks. Primary outcome measures were visual analog scale (VAS) and DNIC function. RESULTS. One week of EA had no clinical important improvement in VAS and DNIC function in all three groups (P>0.05). After 2 weeks” treatment, changes from baseline showed that VAS (strong EA: 2.97, SD 0.10, P<0.0001; weak EA: 2.75, SD 0.15, P <0.0001; sham EA: 1.19, SD 0.14, P<0.0001) and DNIC (strong EA: −14.85, SD 0.16, P<0.0001; weak EA: −4.75, SD 0.28, P<0.0001; sham EA: −1.43, SD 0.24, P<0.0001) were significantly improved in all three groups. Compared with sham EA, weak EA (3.8, 95%CI 3.45 to 4.15) and strong EA (13.54, 95%CI 13.23 to 13.85) were better in improving DNIC function. Compared with weak EA, strong EA were better in enhancing DNIC function (9.73, 95%CI 9.44 to 10.02), as well as in reducing VAS. CONCLUSIONS. In conclusion, EA should be administered 2 weeks to exerting significant effect on KOA. Strong EA was better than weak or sham EA in alleviating the intensity of pain and inhibiting the acute-to-chronic pain transition of KOA

Background. The different biodegradable local antibiotic delivery systems are widely used in recent years. The aim of this study was to evaluate the bactericidal activity antibiotic loaded PerOssal pellet in vitro and its effectiveness in the treatment of Staphylococcus aureus induced chronic osteomyelitis. Material and methods. MALDI-TOF have been applied to microbiological diagnosis in patient with osteomyelitis. In most cases, Staphylococcus aureus was isolated. In vitro Ceftriaxone-Loaded PerOssal pellet were placed in middle agar plate containing a stock strain of Staphylococcus aureus. Plates were incubated at 37ºC for 24 hours. The zones of bacterial inhibition were recorded after 24, 48 and 72 hours of incubation. In vivo evaluation was performed by prospectively studying of 21 patients with a clinically and bacteriologically diagnosed Staphylococcus aureus induced osteomyelitis. Mean age was 38±4,2(26 to 53)). After radical surgical debridement and ultrasound cavitation, the bone cavity was full filled with Perosal pellets loaded with different antibiotics depending from the antibiotic sensitivity test. Endpoints were the absence of clinical manifestation of infection or disease recurrence, no need for further surgery. Results. In vitro showed after 24 hrs inhibition zone was 4,2 х 4,9 cm, after 72 hrs the inhibition zone was increased till 7,6 х 8,4 cm. During the subsequent time, there were no changes. Results of the clinical study evidenced no signs of infection in 18 patients (86% (CI 69,8;100)) (p<0,05) at the follow up, while 3 (14%(CI 0;30,2)) (p<0,05) subjects showed infection recurrence at 6 months from operation and 2 of them needed further surgical procedures. Conclusion. PerOssal as an antibiotic carrier stabilizes the action of the antibiotic. This antibiotic carrier system allows to choose an antibiotic individually for each patient according to the antibiotic sensitivity test and can be successfully used in clinical cases of osteomyelitis

Introduction and Objective

Osteoarthritis of the knee joint is common in old age population in every part of world. Pain is the major source of disability in patients with osteoarthritis of the knee joint. Subchondral bone marrow is richly innervated with nociceptive pain fibers and may be a source of pain in patients with symptomatic degenerative joint disease. Current therapy for managing bone marrow oedema is core decompression (CD), combining core decompression and injection of hydroxyapatite cement or autologus chondrocyte supplementtion. But all of this work has been done in femoral head and authors documented good result with minimal complication. There are various studies in literature suggesting treatment to repair BME by restoring support and relieving abnormal stresses with accepted internal fixation and bone stimulating surgical techniques in relieving knee OA pain. In this study, we present efficacy of knee arthroscopy with adjunctive core decompression and supplementation with structural scaffold to improve self-rated visual analog scale (VAS) pain scores, rate of conversion to arthroplasty, and patient satisfaction levels.

In order to determine the usefulness of MRI in assessing autologous chondrocyte implantation (ACI) the first 57 patients (81 chondral lesions) with a 12-month review were evaluated clinically and with specialised MRI at three and 12 months.

Improvement 12 months after operation was found subjectively (37.6 to 51.9) and in knee function levels (from 85% International Cartilage Repair Society (ICRS) III/IV to 61% I/II). The International Knee Documentation Committee (IKDC) scores showed an initial deterioration at three months (56% IKDC A/B) but marked improvement at 12 months (88% A/B).

The MRI at three months showed 82% of patients with at least 50% defect fill, 59% with a normal or nearly normal signal at repair sites, 71% with a mild or no effusion and 80% with a mild or no underlying bone-marrow oedema. These improved at 12 months to 93%, 93%, 94% and 91%, respectively.

The overall MR score at 12 months suggested production of normal or nearly normal cartilage in 82%, corresponding to a subjective improvement in 81% of patients and 88% IKDC A/B scores. Second-look surgery and biopsies in 15 patients (22 lesions) showed a moderate correlation of MRI with visual scoring; 70% of biopsies showed hyaline and hyaline-like cartilage. Thus, MRI at 12 months is a reasonable non-invasive means of assessment of ACI.

Summary Statement

Preoperative bone-marrow-derived cell mobilization by G-CSF is a safe orthopaedic procedure and allows circulation in the blood of high numbers of CD34+ve cells, promoting osseointegration of a bone substitute.

Intra-articular injection is a common way to deliver biologics to joints, but their effectiveness is limited by rapid clearance from the joint space. This barrier can be overcome by genetically modifying cells within the joint such that they produce anti-arthritic gene products endogenously, thereby achieving sustained, therapeutic, intra-articular concentrations of the transgene products without re-dosing. A variety of non-viral and viral vectors have been subjected to preclinical testing to evaluate their suitability for delivering genes to joints. The first transfer of a gene to a human joint used an ex vivo protocol involving retrovirally transduced, autologous, synovial fibroblasts. Recent advances in vector technology allow in vivo delivery using adeno-associated virus (AAV). We have developed an AAV vector encoding the interleukin-1 receptor antagonist (AAV.IL-1Ra) for injection into joints with osteoarthritis (OA). It showed efficacy and safety in equine and rat models of OA, leading to a recently-completed, investigator-initiated, Phase I, dose-escalation clinical trial in 9 subjects with mid-stage OA of the knee (. ClinicalTrials.gov. Identifier: NCT02790723). Three cohorts of three subjects with mild to moderate OA in the index knee were injected intra-articularly under ultrasound guidance with a low (10e11 viral genomes) medium (10e12 viral genomes) or high (10e13 viral genomes) dose of AAV.IL-1Ra and followed for one year. The data confirm safety, with evidence of sustained intra-articular expression of IL-1Ra and a clinical response in certain subjects. Funding for a subsequent Phase Ib trial involving 50 subjects (. ClinicalTrials.gov. Identifier: NCT05835895), expected to start later this year, has been acquired. Progress in this area has stimulated commercial activity and there are now at least seven different companies developing gene therapies for OA and a number of clinical trials are in progress. Acknowledgement: Clinical trial funded by US Department of Defense Clinical Trial Award W81XWH-16-1-0540

Due to the presence of megakaryocytes, platelets and clotting factors, bone marrow aspirate (BMA) tends to coagulate. For the first time, starting from our previous studies on mesenchymal vertebral stem cells, it has been hypothesized that coagulated BMA represents a safe and effective autologous biological scaffold for bone regeneration in spinal surgery. The present research involved advanced preclinical in vitro models and the execution of a pilot clinical study. Evaluation of cell morphology, growth kinetics, immunophenotyping, clonogenicity, trilineage-differentiation, growth-factors and HOX and TALE gene expression were analyzed on clotted- and un-clotted human V-BMA. In parallel, a pilot clinical study on ten patients with degenerative spine diseases submitted to instrumented posterior arthrodesis, is ongoing to assess the ability of clotted-V-BMA to improve spinal fusion at 6- and 12-months follow-up. Results demonstrated that clotted-V-BMA have significantly higher growth-factor expression and mesenchymal stem cell (MSCs) viability, homogeneity, clonogenicity, and ability to differentiate towards the osteogenic phenotype than un-clotted-V-BMA. Clotted-V-BMA also highlighted significant reduced expression of PBX1 and of MEIS3 genes negatively involved in osteoblast maturation and differentiation. From December 2020, eight patients have already been enrolled with first promising results that will be finally evaluated in the next two months. The application of V-BMA-clot as carrier of progenitors and cytokines and as natural scaffold with a structural texture represents a point-of-care orthobiologic product to improve spinal fusion. Clinical application seems to be efficacy, and we will confirm and strengthen these data with the final results of the pilot clinical study

Translational models for OA have used a variety of small (mouse, rat) and large (sheep, pig) animal models to evaluate the efficacy of a specific therapy. Clinical trials based on the results of these animal models have yielded mixed results with respect to the treatment of the disease. Due to greater stringency in EU regulations in the use of animal models for research, ex vivo models of OA (e.g. cartilage explants, bioreactors) are being developed to mimic human joint motion as well as the inflammatory milieu (e.g. IL-1β) that can be used to understand efficacy of therapy in a physiological environment. The development of these models can enable therapies to undergo clinical trials in patients without the necessity for long-term animal studies. This presentation will describe the state of the art in this field and will discuss whether there is potential to speed up translation from bench to bedside in the future

The aim of the ongoing projects was to demonstrate the efficacy of autologous bone marrow derived stem cells (MSC) combined with biomaterial to induced new bone formation in a randomized multicenter controlled clinical trial. Patients with a need for bone reconstruction of residual edentulous ridges in both the mandible and maxilla due to bone defects with a vertical loss of alveolar bone volume and/or knife edge ridges (≤ than 4,5 mm) unable to provide adequate primary stabilization for dental implants were included in the clinical study. Autologous bone marrow MSC were expanded, loaded on BCP and used to augment the alveolar ridges. After five months bone biopsies were harvested at the implant position site and implants were installed in the regenerated bone. The implants were loaded after 8–12 weeks. Safety, efficacy, quality of life and success/survival were assessed. Five clinical centers, 4 different countries participated. Bone grafts harvested from the ramus of the mandibles were used as control in the projects

High tibial osteotomy (HTO) is a joint preserving alternative to knee replacement for medial tibiofemoral osteoarthritis in younger, more active patients. The procedure is technically challenging and limited also by ‘one size fits all’ plates which can result in patient discomfort necessitating plate removal. This clinical trial evaluated A novel custom-made HTO system – TOKA (3D Metal Printing LTD, Bath, UK) for accuracy of osteotomy correction and improvements in clinical outcome scores. The investigation was a single-arm single-centre prospective clinical trial (IRCCS Istituto Ortopedico Rizzoli; ClinicalTrials.gov NCT04574570), with recruitment of 25 patients (19M/6F; average age: 54.4 years; average BMI: 26.8), all of whom received the TOKA HTO 3D planning and surgery. All patients were predominantly diagnosed with isolated medial knee osteoarthritis and with a varus deformity under 20°. Patients were CT scanned pre- and post-operatively for 3D virtual planning and correctional assessment. All surgeries were performed by the lead clinical investigator – a consultant knee surgeon with a specialist interest in and clinical experience of HTO. On average, Knee Society Scores (KSS) improved significantly (p<0.001) by 27.6, 31.2 and 37.2 percentage points respectively by 3-, 6- and 12-months post-surgery respectively. Other measures assessed during the study (KOOS, EQ5D) produced similar increases. Our early experience using custom implants is extremely promising. We believe the reduced profile of the plate, as well as the reduced invasiveness and ease of surgery contributed to faster patient recovery, and improved outcome scores compared to conventional techniques. These clinical outcome results compare very favourably other case-series with published KOOS scores using different devices

The aim of this scoping review is to understand the extent and type of evidence in relation to the use of guided growth for correcting rotational deformities of long bones. Guided growth is routinely used to correct angular deformities in long bones in children. It has also been proven to be a viable method to correct rotational deformities, but the concept is not yet fully examined. Databases searched include Medline, Embase, Cochrane Library, Web of Science and Google Scholar. All identified citations were uploaded into Rayyan.ai and screened by at least two reviewers. The search resulted in 3569 hits. 14 studies were included: 1 review, 3 clinical trials and 10 pre-clinical trials. Clinical trials: a total of 21 children (32 femurs and 5 tibiae) were included. Surgical methods were 2 canulated screws connected by cable, PediPlates obliquely oriented, and separated Hinge Plates connected by FiberTape. Rotation was achieved in all but 1 child. Adverse effects reported include limb length discrepancy (LLD), knee stiffness and rebound of rotation after removal of tethers. 2 pre-clinical studies were ex-vivo studies, 1 using 8-plates on Sawbones and 1 using a novel z-shaped plates on human cadaver femurs. There were 5 lapine studies (2 using femoral plates, 2 using tibial plates and 1 using an external device on tibia), 1 ovine (external device on tibia), 1 bovine (screws and cable on metacarp) and a case-report on a dog that had an external device spanning from femur to tibia. Rotation was achieved in all studies. Adverse effects reported include implant extrusions, LLD, articular deformities, joint stiffness and rebound. All included studies conclude that guided growth is a viable treatment for rotational deformities of long bones, but there is great variation in models and surgical methods used, and in reported adverse effects

Nerve transfer is an emerging treatment to restore upper limb function in people with tetraplegia. The objective of this study is to examine if a flexible collage sheet (FCS) can act as epineurial-like substitute to promote nerve repair in nerve transfer. A preclinical study using FCS was conducted in a rat model of sciatic nerve transection. A prospective case series study of nerve transfer was conducted in patients with C5-C8 tetraplegia who received nerve transfer to restore upper limb function. Motor function in the upper limb was assessed pre-treatment, and at 6-,12-, and 24-months post-treatment. Macroscopic assessment in preclinical model showed nerve healing by FCS without encapsulation or adhesions. Microscopic examination revealed that a new, vascularised epineurium-like layer was observed at the FCS treatment sites, with no evidence of inflammatory reaction or nerve compression. Treatment with FCS resulted in well-organised nerve fibres with dense neurofilaments distal to the coaptation site. Axon counts performed proximal and distal to the coaptation site showed that 97% of proximal axon count of myelinated axons regenerated across the coaptation site after treatment with CND. In the proof of concept clinical study 17 nerve transfers were performed in five patients. Nerve transfers included procedures to restore triceps function (N=4), wrist/finger/thumb extension (N=6) and finger flexion (N=7). Functional motor recovery (MRC ≥3) was achieved in 76% and 88% of transfers at 12 and 24 months, respectively. The preclinical study showed that FCS mimics epineurium and enable to repair nerve resembled to normal nerve tissue. Clinical study showed that patients received nerve transfer with FCS experienced consistent and early return of motor function in target muscles. These results provide proof of concept evidence that CND functions as an epineurial substitute and is promising for use in nerve transfer surgery