Safety and efficacy of matrix-associated autologous chondrocyte implantation with spheroid technology is independent of spheroid dose after 4 years.

PURPOSE: The aim of this study was to investigate the effect of product dose in autologous chondrocyte implantation (ACI) for the treatment of full-thickness cartilage defects of the knee and to assess its influence on clinical and morphological mid-term outcome. METHODS: Seventy-five patients were included in this single-blind, randomised, prospective, controlled clinical trial. Patients were assigned randomly to three different dose groups [low (3-7 spheroids/cm2), medium (10-30 spheroids/cm2), or high (40-70 spheroids/cm2)] and assessed using standardised clinical and morphological scoring systems (KOOS, IKDC, MOCART) for 4 years following the intervention. RESULTS: The analysis population comprised 75 patients (22 women, 53 men) aged 34 ± 9 years. Defect sizes ranged from 2 to 10 cm2 following intraoperative debridement. The assessment of the primary variable 'overall KOOS' showed a statistically significant improvement, compared with baseline, for each dose group, i.e., at baseline the mean 'overall KOOS' scores were 60.4 ± 13.6, 59.6 ± 15.4, and 51.1 ± 15.4 for the low-, medium-, and high-dose groups, respectively, and 57.0 ± 15.2 for 'all patients'. After 48 months those values improved to 80.0 ± 14.7, 84.0 ± 14.9, and 66.9 ± 21.5 in the respective dose groups and 77.1 ± 18.6 for 'all patients'. Pairwise comparisons of these dose groups did not reveal any statistically significant differences. Likewise, assessment of the subjective IKDC score revealed no statistically significant differences between the three dose groups up to the 48-month visit. However, between 12 and 48 months there was a low, but steady, improvement in the low-dose group and a substantial amelioration in the medium-dose group. The mean MOCART total scores 3 months after treatment were 59.8 ± 10.9, 64.5 ± 10.3, and 64.7 ± 9.4 for the low-, medium-, and high-dose groups, and 62.9 ± 10.3 for 'all patients'; 48 months after treatment these were 73.9 ± 13.1, 78.0 ± 12.4, and 74.3 ± 14.0 for the respective dose groups and 75.5 ± 13.1 for 'all patients'. CONCLUSIONS: Results of this study confirm the efficacy and safety of the applied "advanced therapy medicinal product"; no dose dependence was found either for the incidence or for the severity of any adverse reactions. All doses applied in the present study led to significant clinical improvement over time and can therefore be regarded as effective doses. The influence of product doses in the range investigated seems to be low and can be neglected. Thus, the authorised dose range of 10-70 spheroids/cm2 confirmed by this clinical trial offers a broad therapeutic window for the surgeon applying the product, thereby reducing the risk of over- or underdosing. LEVEL OF EVIDENCE: I.

Clinical outcome and success rates of ACI for cartilage defects of the patella: a subgroup analysis from a controlled randomized clinical phase II trial (CODIS study).

AIM: Cartilage defects of the patella are considered as a problematic entity. Purpose of the present study was to evaluate the outcome of patients treated with autologous chondrocyte implantation (ACI) for cartilage defects of the patella in comparison to patient with defects of the femoral condyles. PATIENTS AND METHODS: 73 patients with a follow-up of 5 years have been included in this subgroup analysis of the randomized controlled clinical trial (RCT). In dependence of defect location, patients were divided into two groups [patella defects (n = 45) and femoral condyle defects (n = 28)]. Clinical outcome was evaluated by the means of the KOOS score at baseline and 6 weeks, 3, 6, 12, 18, 24, 36, 48 and 60 months following ACI. RESULTS: "Responder rate" at 60 months (improvement from baseline of > 7 points in the KOOS score) in patients with patella defects was 86.2%. All scores showed a significant improvement from baseline. While overall KOOS score at 60 months was 81.9 (SD 18.6) points in femoral condyle defects, a mean of 82.6 (SD 14.0) was observed in patella defects (p = 0.2483). CONCLUSION: ACI seems an appropriate surgical treatment for cartilage defects of the patella leading to a high success rate. In this study, the clinical outcome in patients with patellar defects was even better than the already excellent results in patients with defects of the femoral condyle even though the study included relatively large defect sizes for both groups (mean defect size 6.0 ± 1.7 and 5.4 ± 1.6 for femur and patella, respectively).

Comparative survey of canine parvovirus, canine distemper virus and canine enteric coronavirus infection in free-ranging wolves of central Italy and south-eastern France.

Diseases likely affect large carnivore demography and can hinder conservation efforts. We considered three highly contagious viruses that infect a wide range of domestic and wild mammals: canine parvovirus type 2 (CPV-2), canine distemper virus (CDV) and canine enteric coronaviruses (CECoV). Infection by either one of these viruses can affect populations through increased mortality and/or decreased general health. We investigated infection in the wolf populations of Abruzzo, Lazio e Molise National Park (PNALM), Italy, and of Mercantour National Park (PNM), France. Faecal samples were collected during one winter, from October to March, from four packs in PNALM (n = 79) and from four packs in PNM (n = 66). We screened samples for specific sequences of viral nucleic acids. To our knowledge, our study is the first documented report of CECoV infection in wolves outside Alaska, and of the large-scale occurrence of CPV-2 in European wolf populations. The results suggest that CPV-2 is enzootic in the population of PNALM, but not in PNM and that CECoV is episodic in both areas. We did not detect CDV. Our findings suggest that density and spatial distribution of susceptible hosts, in particular free-ranging dogs, can be important factors influencing infections in wolves. This comparative study is an important step in evaluating the nature of possible disease threats in the studied wolf populations. Recent emergence of new viral strains in Europe additionally strengthens the need for proactive monitoring of wolves and other susceptible sympatric species for viral threats and other impairing infections.

Restoring speech intelligibility for hearing aid users with deep learning.

Almost half a billion people world-wide suffer from disabling hearing loss. While hearing aids can partially compensate for this, a large proportion of users struggle to understand speech in situations with background noise. Here, we present a deep learning-based algorithm that selectively suppresses noise while maintaining speech signals. The algorithm restores speech intelligibility for hearing aid users to the level of control subjects with normal hearing. It consists of a deep network that is trained on a large custom database of noisy speech signals and is further optimized by a neural architecture search, using a novel deep learning-based metric for speech intelligibility. The network achieves state-of-the-art denoising on a range of human-graded assessments, generalizes across different noise categories and-in contrast to classic beamforming approaches-operates on a single microphone. The system runs in real time on a laptop, suggesting that large-scale deployment on hearing aid chips could be achieved within a few years. Deep learning-based denoising therefore holds the potential to improve the quality of life of millions of hearing impaired people soon.

Non-intrusive deep learning-based computational speech metrics with high-accuracy across a wide range of acoustic scenes.

Speech with high sound quality and little noise is central to many of our communication tools, including calls, video conferencing and hearing aids. While human ratings provide the best measure of sound quality, they are costly and time-intensive to gather, thus computational metrics are typically used instead. Here we present a non-intrusive, deep learning-based metric that takes only a sound sample as an input and returns ratings in three categories: overall quality, noise, and sound quality. This metric is available via a web API and is composed of a deep neural network ensemble with 5 networks that use either ResNet-26 architectures with STFT inputs or fully-connected networks with wav2vec features as inputs. The networks are trained and tested on over 1 million crowd-sourced human sound ratings across the three categories. Correlations of our metric with human ratings exceed or match other state-of-the-art metrics on 51 out of 56 benchmark scenes, while not requiring clean speech reference samples as opposed to metrics that are performing well on the other 5 scenes. The benchmark scenes represent a wide variety of acoustic environments and a large selection of post-processing methods that include classical methods (e.g. Wiener-filtering) and newer deep-learning methods.

Safety and Efficacy of Matrix-Associated Autologous Chondrocyte Implantation With Spheroids for Patellofemoral or Tibiofemoral Defects: A 5-Year Follow-up of a Phase 2, Dose-Confirmation Trial.

BACKGROUND: Matrix-associated autologous chondrocyte implantation (ACI) is a well-established treatment for cartilage defects. High-level evidence at midterm follow-up is limited, especially for ACI using spheroids (spherical aggregates of ex vivo expanded human autologous chondrocytes and self-synthesized extracellular matrix). PURPOSE: To assess the safety and efficacy of 3-dimensional matrix-associated ACI using spheroids to treat medium to large cartilage defects on different locations in the knee joint (patella, trochlea, and femoral condyle) at 5-year follow-up. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 75 patients aged 18 to 50 years with medium to large (4-10 cm2), isolated, single cartilage defects, International Cartilage Repair Society grade 3 or 4, were randomized on a single-blind basis to treatment with ACI at 1 of 3 dose levels: 3 to 7, 10 to 30, or 40 to 70 spheroids/cm2 of defect size. Outcomes were assessed via changes from baseline Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee score, and modified Lysholm assessments at 1- and 5-year follow-up. Structural repair was evaluated using MOCART (magnetic resonance observation of cartilage repair tissue) score. Treatment-related adverse events were assessed up to 5 years for all patients. The overall KOOS at 12 months was assessed for superiority versus baseline in a 1-sample, 2-sided t test. RESULTS: A total of 73 patients were treated: 24 in the low-dose group, 25 in the medium-dose group, and 24 in the high-dose group. The overall KOOS improved from 57.0 ± 15.2 at baseline to 73.4 ± 17.3 at 1-year follow-up (P < .0001) and 76.9 ± 19.3 at 5-year follow-up (P < .0001), independent of the applied dose. The different defect locations (patella, trochlea, and weightbearing part of the femoral condyles; P = .2216) and defect sizes (P = .8706) showed comparable clinical improvement. No differences between the various doses were observed. The overall treatment failure rate until 5 years was 4%. Most treatment-related adverse events occurred within the first 12 months after implantation, with the most frequent adverse reactions being joint effusion (n = 71), arthralgia (n = 14), and joint swelling (n = 9). CONCLUSION: ACI using spheroids was safe and effective for defect sizes up to 10 cm2 and showed maintenance of efficacy up to 5 years for all 3 doses that were investigated. REGISTRATION: NCT01225575 (ClinicalTrials.gov identifier); 2009-016816-20 (EudraCT number).

Research and Development of Self-Contained Water Injection Systems.

Reducing fuel consumption and thus CO2 emissions is one of the most urgent tasks of current research in the field of internal combustion engines. Water Injection has proven its benefits to increase power or optimize fuel consumption of passenger cars. This technology enables knock mitigation to either increase the engine power output or raise the compression ratio and efficiency while enabling λ = 1 operation in the complete engine map to meet future emission targets. Current systems have limited container capacity. It is necessary to refill the water tank regularly. This also means that we cannot get the benefits of an engine with a higher compression ratio. For this reason, the self-contained system was investigated. This article is a methodology for finding the right design of a self-contained water injection system, but also a vehicle test that proves the function.

The minimally invasive anterolateral approach combined with hip onlay resurfacing.

OBJECTIVE: Minimally invasive anterolateral approach in hip resurfacing with complete preservation of muscular integrity. INDICATIONS: Primary or secondary osteoarthritis of the hip. APPROACH: None. Onlay implant: Females>55 years with osteoporosis. Males>60 years with osteoporosis. Severe varus deformity (CCD [collodiaphyseal] angle<100 degrees). History of metal allergy. Clinically relevant renal insufficiency. Radiologic appearance of avascular necrosis stage 3 and 4 according to Ficat. Femoral head cysts>1 cm in diameter. SURGICAL TECHNIQUE: Supine position with possible overextension of the hip, longitudinal incision along the intermuscular septum and blunt intermuscular dissection between gluteus medius and tensor fasciae latae, partial resection of the anterior capsule and anterior dislocation of the hip with complete proximal release of the capsule. Dislocation of the femoral head and dorsal positioning, reaming of the acetabulum to implant the cementless acetabular component, exposition and reaming of the femoral head in extension/adduction and external rotation, implantation of the cemented onlay endoprosthesis. POSTOPERATIVE MANAGEMENT: Prophylaxis of thromboembolism and periarticular ossification. Rehabilitation with weight bearing as tolerated starting on the day of surgery, ergometer training from day 4 after surgery. RESULTS: 31 patients with osteoarthritis underwent onlay resurfacing via a minimally invasive approach. The Harris Hip Score improved from 43.9 to 97.1 at 12 months after surgery. Adverse events such as fracture, dislocation, nerve or muscle lesions did not occur, and clinically significant thromboembolism or infection was not observed.

High hydrostatic pressure, a novel approach in orthopedic surgical oncology to disinfect bone, tendons and cartilage.

High hydrostatic pressure (HHP) is widely used in the food processing industry, for example to inactivate vegetative microorganisms in meat products, milk and juice, thereby avoiding the addition of any chemical preservatives. Besides this, HHP is also an attractive novel approach to effectively kill vegetative microorganisms or tumor cells in bone, cartilage and tendon ex vivo while leaving the tissues' mechanical properties unimpaired, thus allowing reimplantation of the resected tissue explants. In contrast, sterilization by gamma irradiation and thermal or chemical inactivation of potentially infected autografts, allografts and other biomaterials considered for tissue regeneration and reconstruction is often associated with deterioration of the mechanical, physical and biological properties of the implant. HHP technology is now in preclinical testing with the aim of disinfecting/devitalizing grafts in order to inactivate both vegetative microorganisms and tumor cells in resected bone tissue segments, eventually allowing reimplantation of resected bone segments initially afflicted with osteomyelitis or tumors. The technical advantages, state-of-the-art, and potential application of HHP in orthopedic surgery are reviewed.

[Extracorporeal high hydrostatic pressure as a new technology for the disinfection of infected bone specimens]]. / Extrakorporale hydrostatische Hochdruckbehandlung als neues Verfahren zur Desinfektion infizierter Knochenpräparate.

BACKGROUND: Allogeneic bone transplantation is at risk of infection, and established disinfection methods typically compromise bone quality. High hydrostatic pressure (HHP) is well established for disinfection in food technology, and also it does protect biomechanical and biological properties of bone. This study is the first investigation of HHP regarding disinfection of bone biopsies. MATERIALS AND METHODS: Bone biopsies of 34 patients with chronic infections were subjected to HHP and assessed for persisting bacterial growth. In series 1, bone biopsies were proceeded directly to HHP (10 min; maximal pressure Pmax 600 MPa). In series 2, HHP was applied after 5-day incubation in growth media (10 min or 2x30 min; Pmax 600 MPa). Furthermore, HHP-induced changes of bacterial morphology on artificially infected bone samples were evaluated by scanning electron microscopy (SEM). RESULTS: For series 1, 71% of the bone samples were sterilised by HHP (n=17), compared to 38% of the untreated control samples, which were obtained during the same surgery (n=8). For series 2, after prior incubation, HHP disinfected 7% of the bone specimens (n=55), all control samples showed bacterial growth (n=33). Destruction of cell wall integrity of Gram-negative strains was observed by SEM. CONCLUSION: The effectiveness of HHP for bone disinfection should be improved by optimising treatment parameters. Infections with barosensitive Gram-negative bacteria or yeast might represent possible clinical indications.

Quantitative analysis of the impact of short-time high hydrostatic pressure on bone tumor-associated proteases.

In orthopedic surgery, sterilization of bone used for reconstruction of osteoarticular defects caused by malignant tumors is carried out in various ways. At present, to devitalize tumor-bearing osteochondral segments, extracorporeal irradiation or autoclaving is mainly used, although both methods have substantial disadvantages, leading to a significant loss of biomechanical and biological integrity of the bone. As an alternative approach, a new technology to achieve bone sterilization, the high hydrostatic pressure (HHP) treatment of bone, has been suggested, which is currently being preclinically tested. This novel technique leads to the inactivation of tumor cells without impairing biomechanical properties of the bone, cartilage, or tendons. HHP may not only exert an effect on tumor and normal cells present in the bone but also on tumor-associated proteases released by these cells, which are conductive to tumor bone turnover. In order to investigate this, proteolytic key enzymes, e.g. MMP-9, uPA, t-PA, plasmin, trypsin, and thrombin were subjected to HHP

Safety of three different product doses in autologous chondrocyte implantation: results of a prospective, randomised, controlled trial.

BACKGROUND: This study was conducted to assess the efficacy and safety of the three dose levels of the three-dimensional autologous chondrocyte implantation product chondrosphere® in the treatment of cartilage defects (4-10 cm2) of knee joints. We hereby report the safety results for a 36-month post-treatment observation period. METHODS: This was a prospective phase II trial with a clinical intervention comprising biopsy for culturing spheroids and their subsequent administration (level of evidence: I). Patients' knee defects were investigated by arthroscopy, and a cartilage biopsy was taken for culturing. Patients were randomised, on a single-blind basis, to treatment at the dose levels 3-7 (low), 10-30 (medium) or 40-70 (high) spheroids per square centimetre. Assessment (adverse events, vital signs, electrocardiography, physical examination, concomitant medication and laboratory values) took place 1.5, 3, 6, 12, 24 and 36 months after chondrocyte implantation. RESULTS: Seventy-five patients were included and 73 treated. The incidence of adverse events, of patients with adverse events and of patients with treatment-related adverse events showed no relevant difference between the treatment groups. There were no fatal adverse events, no adverse events led to premature withdrawal from the trial and none led to permanent sequelae. Two patients experienced serious adverse events considered related to the study treatment: arthralgia 2-3 years after implantation and chondropathy 1 and 2 years after implantation. CONCLUSIONS: The treatment with chondrosphere® was generally well tolerated. No relationship was detected between any safety criteria and the dose level: Differences between the dose groups in the incidence of any adverse events, and in numbers of patients with treatment-related adverse events, were insubstantial. TRIAL REGISTRATION: clinicaltrials.gov, NCT01225575 .

Growth promoting in vitro effect of synthetic cyclic RGD-peptides on human osteoblast-like cells attached to cancellous bone.

In tissue engineering, the application of biofunctional compounds on biomaterials such as integrin binding RGD-peptides has gained growing interest. Anchorage-dependent cells like osteoblasts bind to these peptides thus ameliorating the integration of a synthetic implant. In case sterilized bone grafts are used as substitutes for reconstruction of bone defects, the ingrowth of the implanted bone is often disturbed because of severe pretreatment such as irradiation or autoclaving, impairing the biological and mechanical properties of the bone. We report for the first time on the in vitro coating of the surface of freshly resected, cleaned bone discs with synthetic, cyclic RGD-peptides. For this approach, two different RGD-peptides were used, one containing two phosphonate anchors, the other peptide four of these binding moieties to allow efficient association of these reactive RGD-peptides to the inorganic bone matrix. Human osteoblast-like cells were cultured on RGD-coated bone discs and the adherence and growth of the cells were analyzed. Coating of bone discs with RGD-peptides did not improve the adhesion rate of osteoblast-like cells to the discs but significantly (up to 40%) accelerated growth of these cells within 8 days after attachment. This effect points to pretreatment of bone implants, especially at the critical interface area between the implanted bone and the non-resected residual bone structure, before re-implantation in order to stimulate and enhance osteointegration of a bone implant.

Effect of extracorporeal high hydrostatic pressure on cellular outgrowth from tumor-afflicted bone.

At present, in orthopedic surgery, the reconstruction of bone defects following resection of malignant tumors is effected by several methods. The irradiation and autoclaving of bone segments are the 2 methods of choice to extracorporeally devitalize the resected tumor-bearing bone segments. An alternative, gentle method of devitalizing bone-associated cells by exposing normal and tumor cells to extracorporeal high hydrostatic pressure (HHP) has been introduced. The aim of this study was to examine the ex vivo effect of HHP on the cell growth of normal and tumor-afflicted freshly-resected small human bone segments. For this, tumor-afflicted human bone segments of 5 x 5 x 5 mm in size, obtained during surgery from 14 patients suffering from chondrosarcoma or osteosarcoma, in comparison to bone segments obtained from 36 patients with normal bone, disease were exposed to HHP levels of 0, 150 and 300 MPa for 10 min at 37 degrees C. Following HHP-treatment, the specimens were placed into cell culture and observed for cell outgrowth up to 50 days. In control samples (0 MPa), rapid outgrowth of cells was observed. HHP-treatment of 150 MPa however, resulted in reduced outgrowth of cells from these bone specimens; at 300 MPa, no outgrowth of cells was detected. Light microscopy and standard histological examination showed morphological changes between control samples (0 MPa) and 150 MPa. Our results suggest that the treatment of tumor-afflicted bone and the associated cartilage by HHP leads to the devitalization of bone cells concomitant with complete impairment of cellular outgrowth, a precondition for re-implantation of the HHP-treated bone.

Biomechanical investigation of the effect of high hydrostatic pressure treatment on the mechanical properties of human bone.

Several methods are available for reconstruction of bone defects due to malignant tumors. To extracorporally devitalize resected tumor-bearing bone segments two methods, that is, extracorporal irradiation or autoclaving, are available up to now. However, both methods have substantial disadvantages like decrease of bone's mechanical strength. To develop an alternative method for tumor inactivation in skeletal segments, high hydrostatic pressure (HHP) was applied. Previous investigations have shown that human normal and tumor cell lines as well as tumor-afflicted human bone specimens were irreversibly damaged at 350 MPa when subjected to HHP. This study was aimed to examine the alterations of biomechanical properties of human bone after exposure to HHP. Trabecular and cortical bone specimens were harvested from six pair of fresh-frozen human cadaveric femora. The bone specimens from one side were exposed to different pressure values of 300 or 600 MPa over 10 min. Bone samples from the contralateral sites were used as untreated controls. Biomechanical properties were investigated by a quasi-static compression test for trabecular specimens and by a quasi-static four-point bending test for cortical specimens, respectively. Biomechanical properties of the cortical and trabecular bone did not decrease after exposure to 300 MPa regarding the testing parameters Young's modulus and ultimate strength (200.7 +/- 38.7 MPa for HHP treated cortical bone versus 186.5 +/- 34.3 MPa for the untreated control group). After pressure treatment at 600 MPa Young's modulus and ultimate strength respectively remained almost unchanged in trabecular bone and were reduced about 15% in cortical bone (p < 0.001 and p =0.002, respectively). We anticipate that in orthopedic surgery HHP can serve as a novel, promising methodical approach for tumor cell inactivation, which occurs at pressure levels of about 300 MPa. Thereby immediate reimplantation of treated bone segments by preservation of the essential biomechanical properties of bone could become possible. Even after HHP treatment at 600 MPa the strength of bone only decreases up to 15%.

[Biomechanical properties of articular cartilage after high hydrostatic pressure treatment]. / Biomechanische Eigenschaften von Gelenkknorpel nach hydrostatischer Hochdruckbehandlung.

AIM: Reconstruction of bone defects due to malignant tumors can be realized by several methods. Up to now, two methods, irradiation and autoclaving, are available for extracorporeally devitalizing resected tumor-bearing osteochondral segments. Previous investigations have shown that human normal and tumor cells in culture were irreversibly impaired when subjected to extracorporeal high hydrostatic pressure (HHP) of 350 MPa. The aim of this study was to examine the biomechanical and immunohistochemical properties of cartilage after exposure to HHP MATERIALS AND METHODS: Osteochondral segments of bovine femoral condyles were exposed to pressure of 300 and 600 MPa (n=20 each). Biomechanical and biological properties of untreated and treated segments were evaluated by repetitive ball indention testing and immunohistochemical labelling aggrecan, link protein and collagen II. The contralateral segments served as untreated control. RESULTS: No significant alterations concerning stiffness and relaxation of osteochondral segments even after 600 MPa were observed. Immunohistochemically, staining was positive in all cases and no differences in the labeling pattern of proteoglycanes were observed between untreated and HHP-treated specimens. CONCLUSION: These findings give hope that HHP eventually will be used as a new gentle way of treating resected cartilage and bone without alteration of biomechanical properties to inactivate tumor cells in order to allow autologous reimplantation.

Structural Plasticity Denoises Responses and Improves Learning Speed.

Despite an abundance of computational models for learning of synaptic weights, there has been relatively little research on structural plasticity, i.e., the creation and elimination of synapses. Especially, it is not clear how structural plasticity works in concert with spike-timing-dependent plasticity (STDP) and what advantages their combination offers. Here we present a fairly large-scale functional model that uses leaky integrate-and-fire neurons, STDP, homeostasis, recurrent connections, and structural plasticity to learn the input encoding, the relation between inputs, and to infer missing inputs. Using this model, we compare the error and the amount of noise in the network's responses with and without structural plasticity and the influence of structural plasticity on the learning speed of the network. Using structural plasticity during learning shows good results for learning the representation of input values, i.e., structural plasticity strongly reduces the noise of the response by preventing spikes with a high error. For inferring missing inputs we see similar results, with responses having less noise if the network was trained using structural plasticity. Additionally, using structural plasticity with pruning significantly decreased the time to learn weights suitable for inference. Presumably, this is due to the clearer signal containing less spikes that misrepresent the desired value. Therefore, this work shows that structural plasticity is not only able to improve upon the performance using STDP without structural plasticity but also speeds up learning. Additionally, it addresses the practical problem of limited resources for connectivity that is not only apparent in the mammalian neocortex but also in computer hardware or neuromorphic (brain-inspired) hardware by efficiently pruning synapses without losing performance.

The Effect of Cell Dose on the Early Magnetic Resonance Morphological Outcomes of Autologous Cell Implantation for Articular Cartilage Defects in the Knee: A Randomized Clinical Trial.

BACKGROUND: Although autologous chondrocyte implantation (ACI) has been established as a standard treatment for large full-thickness cartilage defects, the effect of different doses of autologous chondrocyte products on structural outcomes has never been examined. HYPOTHESIS: In ACI, the dose level may have an influence on medium-term magnetic resonance morphological findings after treatment. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 75 patients who underwent ACI using a pure, autologous, third-generation matrix-associated ACI product were divided into 3 groups representing different doses: 3 to 7 spheroids/cm(2), 10 to 30 spheroids/cm(2), and 40 to 70 spheroids/cm(2). Magnetic resonance imaging was performed at 1.5, 3, 6, and 12 months after ACI and was evaluated by the magnetic resonance observation of cartilage repair tissue (MOCART) score and the Knee injury and Osteoarthritis Outcome Score (KOOS). RESULTS: MOCART scores showed improvements after 3 months, with slight dose dependence, and further improvement after 12 months, although without significant dose dependence. The mean MOCART scores after 3 months (0 = worst, 100 = best) were 59.8, 64.5, and 64.7 for the low-, medium-, and high-dose groups, respectively, and 62.9 for all patients; at 12 months, these were 74.1, 74.5, and 68.8 for the respective dose groups and 72.4 for all patients. Several MOCART items (surface of repair tissue, structure of repair tissue, signal intensity of repair tissue, subchondral bone, and synovitis) showed a more rapid response with the medium and high doses than with the low dose, suggesting a potential dose relationship. No significant correlation between the MOCART (overall and subscores) with clinical outcomes as assessed by the overall KOOS was detected at 3- and 12-month assessments. CONCLUSION: This study reveals a trend toward earlier recovery after treatment with higher spheroid doses in terms of better defect filling for full-thickness cartilage defects of the knee, while outcomes after 12 months were similar in all dose groups. However, a correlation with clinical outcomes or the failure rate at 1 year after ACI was not found. A longer follow-up will be required for more definite conclusions on the clinical relevance of ACI cell density to be drawn. REGISTRATION: NCT01225575 (ClinicalTrials.gov identifier); 2009-016816-20 (EudraCT number).