Total knee and hip arthroplasty (TKA and THA) are the most commonly performed surgical procedures, the costs of which constitute a significant healthcare burden. Improving access to care for THA/TKA requires better efficiency. It is hypothesized that this may be possible through a two-stage approach that utilizes prediction of surgical time to enable optimization of operating room (OR) schedules. Data from 499,432 elective unilateral arthroplasty procedures, including 302,490 TKAs, and 196,942 THAs, performed from 2014-2019 was extracted from the American College of Surgeons (ACS) National Surgical and Quality Improvement (NSQIP) database. A deep multilayer perceptron model was trained to predict duration of surgery (DOS) based on pre-operative clinical and biochemical patient factors. A two-stage approach, utilizing predicted DOS from a held out “test” dataset, was utilized to inform the daily OR schedule. The objective function of the optimization was the total OR utilization, with a penalty for overtime. The scheduling problem and constraints were simulated based on a high-volume elective arthroplasty centre in Canada. This approach was compared to current patient scheduling based on mean procedure DOS. Approaches were compared by performing 1000 simulated OR schedules. The predict then optimize approach achieved an 18% increase in OR utilization over the mean regressor. The two-stage approach reduced overtime by 25-minutes per OR day, however it created a 7-minute increase in underutilization. Better objective value was seen in 85.1% of the simulations. With deep learning prediction and mathematical optimization of patient scheduling it is possible to improve overall OR utilization compared to typical scheduling practices. Maximizing utilization of existing healthcare resources can, in limited resource environments, improve patient's access to arthritis care by increasing patient throughput, reducing surgical wait times and in the immediate future, help clear the backlog associated with the COVID-19 pandemic.
Ultrasound speckle tracking is a safe and non-invasive diagnostic tool to measure soft tissue deformation and strain. In orthopaedics, it could have broad application to measure how injury or surgery affects muscle, tendon or ligament biomechanics. However, its application requires custom tuning of the speckle-tracking algorithm then validation against gold-standard reference data. Implementing an experiment to acquire these data takes months and is expensive, and therefore prohibits use for new applications. Here, we present an alternative optimisation approach that automatically finds suitable machine and algorithmic settings without requiring gold-standard reference data. The optimisation routine consisted of two steps. First, convergence of the displacement field was tested to exclude the settings that would not track the underlying tissue motion (e.g. frame rates that were too low). Second, repeatability was maximised through a surrogate optimisation scheme. All settings that could influence the strain calculation were included, ranging from acquisition settings to post-processing smoothing and filtering settings, totalling >1,000,000 combinations of settings. The optimisation criterion minimised the normalised standard deviation between strain maps of repeat measures. The optimisation approach was validated for the medial collateral ligament (MCL) with quasi-static testing on porcine joints (n=3), and dynamic testing on a cadaveric human knee (n=1, female, aged 49). Porcine joints were fully dissected except for the MCL and loaded in a material-testing machine (0 to 3% strain at 0.2 Hz), which was captured using both ultrasound (>14 repeats per specimen) and optical digital image correlation (DIC). For the human cadaveric knee (undissected), 3 repeat ultrasound acquisitions were taken at 18 different anterior/posterior positions over the MCL while the knee was extended/flexed between 0° and 90° in a knee extension rig. Simultaneous optical tracking recorded the position of the ultrasound transducer, knee kinematics and the MCL attachments (which were digitised under direct visualisation post testing). Half of the data collected was used for optimisation of the speckle tracking algorithms for the porcine and human MCLs separately, with the remaining unseen data used as a validation test set.Abstract
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Many factors have been reported to affect the functional survival of OCA transplants, including chondrocyte viability at time of transplantation, rate and extent of allograft bone integration, transplantation techniques, and postoperative rehabilitation protocols and adherence. The objective of this study was to determine the optimal subchondral bone drilling technique by evaluating the effects of hole diameter on the material properties of OCAs while also considering total surface area for potential biologic benefits for cell and vascular ingrowth. Using allograft tissues that would be otherwise discarded in combination with deidentified diagnostic imaging (MRI and CT), a model of a large shell osteochondral allograft was recreated using LS-PrePost and FEBio based on clinically relevant elastic material properties for cortical bone, trabecular bone, cartilage, and hole ingrowth tissue. The 0.8 mesh size model consisted of 4 mm trabecular bone, 4 mm cortical bone, and 3 mm cartilage sections that summed to a cross-sectional area of 1600 mm2 (40 mm x 40 mm). Holes were modeled to be 4mm deep in relation to clinical practice where holes are drilled from the deep margin of subchondral trabecular bone to the cortical subchondral bone plate. To test the biomechanic variations between drill hole sizes, models with hole sizes pertinent to standard-of-care commercially available orthopaedic drill sizes of 1.1mm, 2.4 mm, or 4.0 mm holes were loaded across the top surface over a one second duration and evaluated for effective stress, effective strain, 1st principal strain, and 3rd principal strain in compressive conditions. Results measured effective stress and strain and 1st and 3rd principal strain increased with hole depth. The results of the present FEA modeling study indicate that the larger 4.0 mm diameter holes were associated with greater stresses and strains within OCA shell graft, which may render the allograft at higher risk for mechanical failure. Based on these initial results, the smaller diameter 2.4 mm and 1.1 mm holes will be further investigated to determine optimal number, configuration, and depth of subchondral drilling for OCA preparation for transplantation
Neurological complications in oncological and degenerative spine surgery represent one of the most feared risks of these procedures. Multimodal intraoperative neurophysiological monitoring (IONM) mainly uses methods to detect changes in the patient's neurological status in a timely manner, thus allowing actions that can reverse neurological deficits before they become irreversible. The utopian goal of spinal surgery is the absence of neurological complications while the realistic goal is to optimize the responses to changes in neuromonitoring such that permanent deficits occur less frequently as possible. In 2014, an algorithm was proposed in response to changes in neuromonitoring for deformity corrections in spinal surgery. There are several studies that confirm the positive impact that a checklist has on care. The proposed checklist has been specifically designed for interventions on stable columns which is significantly different from oncological and degenerative surgery. The goal of this project is to provide a checklist for oncological and degenerative spine surgery to improve the quality of care and minimize the risk of neurological deficit through the optimization of clinical decision-making during periods of intraoperative stress or uncertainty. After a literature review on risk factors and recommendations for responding to IONM changes, 3 surveys were administered to 8 surgeons with experience in oncological and degenerative spine surgery from 5 hospitals in Italy. In addition, anesthesiologists, intraoperative neuro-monitoring teams, operating room nurses participated. The members participated in the optimization and final drafting of the checklist. The authors reassessed and modified the checklist during 3 meetings over 9 months, including a clinical validation period using a modified Delphi process. A checklist containing 28 items to be considered in responding to the changes of the IONM was created. The checklist was submitted for inclusion in the new recommendations of the Italian Society of Clinical Neurophysiology (SINC) for intraoperative neurophysiological monitoring. The final checklist represents the consensus of a group of experienced spine surgeons. The checklist includes the most important and high-performance items to consider when responding to IONM changes in patients with an unstable spine. The implementation of this checklist has the potential to improve surgical outcomes and patient safety in the field of spinal surgery.
Scoliosis correction surgery is one of the longest and most complex procedures of all orthopedic surgery. The complication rate is therefore not negligible and is particularly high when the surgery is performed in patients with neuromuscular or connective tissue disease or complex genetic syndromes. In fact, these patients have various comorbidities and organ deficits (respiratory capacity, swallowing / nutrition, heart function, etc.), which can compromise the outcome of the surgery. In these cases, an accurate assessment and preparation for surgery is essential, also making use of external consultants. To make this phase simpler, more effective and homogeneous, a multidisciplinary path of peri-operative optimization is being developed in our Institute, which also includes the possibility of post-operative hospitalization for rehabilitation and recovery. The goal is to improve the basic functional status as much as possible, in order to ensure faster functional recovery and minimize the incidence of peri-operative complications, to be assessed by clinical audit. The path model and the preliminary results on the first patients managed according to the new modality are presented here. The multidisciplinary path involves the execution of the following assessments / interventions: • Pediatric visit with particular attention to the state of the upper airways and the evaluation of chronic or frequent inflammatory states • Cardiological Consultation with Echocardiogram. • Respiratory Function Tests, Blood Gas Analysis and Pneumological Consultation to evaluate indications for preoperative respiratory physiotherapy cycles, Non-Invasive Ventilation (NIV) cycles, Cough Machine. Possible Polysomnography. • Nutrition consultancy to assess the need for nutritional preparation in order to improve muscle trophism. • Consultation of the speech therapist in cases of dysphagia for liquids and / or solids. • Electroencephalogram and Neurological Consultation in epileptic patients. • Physiological consultation in patients already being treated with a cough machine and / or NIV. • Availability of postoperative hospitalization in the rehabilitation center (with skills in respiratory and neurological rehabilitation) for the most complex cases. When all the appropriate assessments have been completed, the anesthetist in charge at our Institute examines the clinical documentation and establishes whether the path can be considered complete and whether the patient is ready for surgery. At the end of the surgery, the patient is admitted to the Post-operative Intensive Care Unit of the Institute. If necessary, a new program of postoperative rehabilitation (respiratory, neuromotor, etc.) is programmed in a specialist reference center. To date, two patients have been referred to the preoperative optimization path: one with Ullrich Congenital Muscular Dystrophy, and one with 6q25 Microdeletion Syndrome. In the first case, the surgery was performed successfully, and the patient was discharged at home. In the second case, after completing the optimization process, the surgery was postponed due to the finding of urethral malformation with the impossibility of bladder catheterization, which made it necessary to proceed with urological surgery first. The preliminary case series presented here is still very limited and does not allow evaluations on the impact of the program on the clinical practice and the complication rate. However, these first experiences made it possible to demonstrate the feasibility of this complex multidisciplinary path in which a network of specialists takes part.
3D-printed orthopedic implants have been gaining popularity in recent years due to the control this manufacturing technique gives the designer over the different design aspects of the implant. This technique allows us to manufacture implants with material properties similar to bone, giving the implant designer the opportunity to address one of the main complications experienced after total hip arthroplasty (THA), i.e. aseptic loosening of the implant. To restore proper function after implant loosening, the implant needs to be replaced. During these revision surgeries, some extra bone is removed along with the implant, further increasing the already present defects, and making it harder to achieve proper mechanical stability with the revision implant. A possible way to limit the increasing loss of bone is the use of biodegradable orthopedic implants that optimize long-term implant stability. These implants need to both optimize the implant such that stress shielding is minimized, and tune the implant degradation rate such that newly formed bone is able to replace the degrading metal in order to maintain a proper bone-implant contact. The hope is that such (partly) degradable implants will lead to a reduction in the size of the bone defects over time, making possible future revisions less likely and less complex. We focused on improving the long-term implant stability of patient-specific acetabular implants for large bone defects and the modeling of their biodegradable behavior. To improve long-term implant stability we implemented a topology optimization approach. A patient-specific finite element model of the hip joint with and without implant was derived from CT-scans to evaluate the performance of the designs during the optimization routine. To evaluate the biodegradation behavior, a quantitative mathematical model was developed to assess the degradation rates of the biodegradable part of the implant. Currently, the biodegradation model has been implemented for magnesium (Mg) implants as a first proof of concept. For a first test case, an optimized implant was found with stress shielding levels below 20% in most regions. The highest stress shielding levels were found at the bone implant interface. The biodegradation model has been validated using experimental data, which includes immersion tests of simple scaffolds created from Commercial Pure Mg. The mass loss of the scaffold is about 0.8 mg/cm2 for the first day of immersion in simulated body fluid (SBF) solution. After the formation of a protective film on the surface of the simple scaffold, the degradation rate starts to slow down. Initial results presented serve as a proof of concept of the developed computational framework for the implant optimization and the implant biodegradation behavior. Currently, timing calibration, benchmarking and validation are taking place. Reducing implant-induced stress shielding, obtaining a better implant integration and reduction of bone defects, by allowing for bone to partially replace the implant over time, are crucial design factors for large bone defect implants. In this research, we have developed in-silico models to investigate these factors. Once validated and coupled, the models will serve as an important tool to find the appropriate biodegradable implant designs and biodegradable metal properties for THA applications, that improve current implant lifetime while ensuring proper mechanical functioning.
Evaluation of different biomaterials is being performed with various methods trying to simulate the closest hostile-like Here we are presenting another approach based on high-output screening of biomaterials, which is based on the strategy of raising the number of readouts obtainable from every specimen at more clinically-relevant conditions. On the contrary to common methods like ISO 10993 or simplified biomechanical tests, the biomaterials enhanced simulation testing (BEST) evaluates specimens without pre-selected biomaterial model, assessing the whole specimen as would happen in the implantation site. Besides reducing the risk of improper conclusions caused by wrong material model choice, the data processing with non-local method intrinsically includes the test history bypassing common challenges usually seen with hereditary integration. For properly designed experiment, readouts might include invariant moduli, viscous stiffness, fluidity, fluid permittivity and diffusivity (without need for pressure-driven separate tests), fluid source, effective channel size, and swelling pressure (if swelling is present) in addition to conventional biomechanical parameters. New solutions in advanced and consistent evaluations for biomaterials allow better risks control, shorten lead development time and costs, and compliant with 3R-strategy (2010/63/EC) and new regulatory requirements (2012/0266/COD in EU and FY2017 regulatory priorities by FDA). The approach shown is able to combine scientifically based tests with multi-purpose protocols to secure patient safety by screening of biomaterials under proper conditions. The authors thank Finnish Agency for Innovations (Tekes) for providing partial financial support.
Low back pain (LBP), caused by intervertebral disc (IVD) degeneration represents one of the most significant socioeconomic conditions facing Western economies. Novel regenerative therapies, however, have the potential to restore function and relieve pain. We have previously shown that stimulation of adipose-derived stem cells (ASCs) with growth differentiation factor-6 (GDF6) promotes differentiation to nucleus pulposus (NP) cells of the IVD, offering a potential treatment for LBP. The aims of this study were to i) elucidate GDF6 cell surface receptor profile and signalling pathways to better understand mechanism of action; and (ii) develop a microparticle (MP) delivery system for GDF6 stimulation of ASCs. GDF6 receptor expression by ASCs (N=6) was profiled through western blot, immunofluorescence (IF) and flow cytometry. Signal transduction through Smad1/5/9 and non-Smad pathways following GDF6 (100ng/ml) stimulation was assessed using western blotting and confirmed using pathway specific blockers and type II receptor sub-unit knockdown using CRISPR. Release kinetics of GDF6 from MPs was calculated (BCA assay, ELISAs) and ASC differentiation to NP cells was assessed. BMPR profiling revealed high BMPR2 expression on ASCs. GDF6 stimulation of ASCs resulted in significant increases in Smad1/5/9 and Erk phosphorylation, but not p38 signalling. Blocking GDF6 signalling confirmed differentiation to NP cells required Smad phosphorylation, but not Erk. GDF6 release from MPs was controlled over 14days
Tendon detachment from its bony insertion is one of the most frequent injuries occurring in the musculoskeletal interface, constituting an unmet challenge in orthopaedics. Tendon-to-bone integration occurs at the enthesis, which is characterized by a complex structure organized in a gradient of cells and microenvironments. Hence, the maintenance of a heterotypic cellular niche is critical for tissue functionality and homeostasis. Replicating this unique complexity constitutes a challenge when addressing tendon-to-bone regeneration and interfacial tissue engineering strategies. Currently, mechanisms presiding to tendon-to-bone interface healing are not yet fully understood, particularly the interactions between tendon and bone cells in the orchestration of interfacial repair versus regeneration. Therefore, this study focused on the hypothesis that interactions between human tendon-derived cells (hTDCs) and pre-osteoblasts (pre-OB) can initiate a cascade of events, potentially leading to interfacial regeneration. Thus, hTDCs and pre-OB (pre-differentiated human adipose-derived stem cells) were used. Herein, five different ratios between basal and osteogenic media (100:0,75:25,50:50,25:75,0:100) were assessed to estimate their influence on cell behaviour and identify the ideal parameters for simultaneously supporting tenogenic and osteogenic differentiation before establishing a co-culture. Tenogenic and osteogenic differentiation were assessed through the expression of tendon and bone markers, mineralization (alizarin red, AZ) and alkaline phosphatase (ALP) quantification. Results showed that hTDCs exhibited osteogenic differentiation potential when cultured in the presence of osteogenic media, as demonstrated by an increase in ALP activity and mineralization. Pre-OB expressed osteogenic markers (OCN, OPN) in all media conditions confirming osteogenic commitment, which was simultaneously confirmed by ALP levels and AZ staining. Thus, three different conditions (100:0, 50:50, 0:100) were chosen for further studies in a direct contact co-culture system. Similarly to single cultures, a significant proliferation was observed in all conditions and mineralization was increased as soon as 7 days of culture. Additionally, osteogenic, tenogenic and interface-relevant markers will be assessed to study the effect of co-culture on phenotype maintenance. In summary, the present work addresses major limitations to clinical translation of cell-based therapies aiming at promoting interfacial regeneration. Particularly, we explored the influence of culture media on the maintenance of tenogenic and osteogenic niches, taking a basic and critical step towards the establishment of more complex cell-based systems. Acknowledgements Authors thank Fundação para a Ciência e Tecnologia in the framework of FCT-POPH-FSE, SFRH/BD/96593/2013 (RCA) and IF/00593/2015 (MEG); and to FCT/MCTES and the FSE/POCH, PD/59/2013 for PD/BD/128088/2016 (IC).
Among the innovative therapeutic techniques in orthopedics, a considerable interest arose around Mesenchymal Stem Cells (MSCs) - based therapies for one-step clinical applications. In order to achieve a better cell targeting at the injury site, these applications would need a specific cell delivery system. Hence, in this study a protocol for an efficient cell delivery based on the rapid cell adhesion on the surface of lyophilized fibroin-coated alginate microcarriers (L-FAMs) was optimized by the Design of Experiment (DoE) method in accordance with the minimum requirements for one-step clinical application. Specific parameters (seeding time, intermittent or not dynamic culture, stirring speed and volume of cell suspension) were combined in 13 different protocols, tested on human Adipose derived stem cells - ASCs (n=3). Cell adhesion rate in term of DNA quantification and metabolic activity of cells adhered on L-FAMs, and their qualitative observations by Calcein Staining were evaluated. The data showed that a suspension of 3.75 × 105 cells/ml and 10 mg/ml of FAMs, 12.3 rpm of stirring speed and 85.6 minutes of seeding time are the most performing combination of parameters. The final protocol was then tested and validated on both hASCs (n=3) and human bone marrow derived stem cells - BMSCs (n=3). The results confirmed a high adhesion rate of cells, homogenously arranged on the surface of L-FAMs without cell cluster formation. Even though further optimizations are still needed, the present protocol may represent the proof of concept for the introduction of L-FAMs as carriers in one-step intraoperative applications.
Objective. Early cell loss of up to 50% is common to in vitro chondrogenesis of mesenchymal stromal cells (MSC) and stimulation of cell proliferation could compensate for this unwanted effect and improve efficacy and tissue yield for cartilage tissue engineering. We recently demonstrated that proliferation is an essential requirement for successful chondrogenesis of MSC, however, how it is regulated is still completely unknown. We therefore aimed to identify signaling pathways involved in the regulation of proliferation during in vitro chondrogenesis and investigated, whether activation of relevant pathways could stimulate proliferation. Design. Human MSC were subjected to in vitro chondrogenesis for up to 42 days under standard conditions in the presence of 10 ng/ml TGF-β. Cells were or were not additionally treated with inhibitors of bone morphogenetic protein (BMP), insulin-like growth factor (IGF) IGF/PI3K, fibroblast growth factor (FGF) or indian hedgehog (IHH) pathways for two or four weeks. To investigate the stimulation of proliferation by exogenous factors, cells were treated with BMP-4, IGF-1, FGF-18 or purmorphamine (small molecule hedgehog agonist). Proliferation was determined by [3H]-thymidine incorporation. Results and Discussion. Quantitative assessment of proliferation revealed that proliferation arrest occurred during condensation up to day 3 and cell division was re-initiated thereafter with a peak on day 28. To test which pathways are relevant for the restart of proliferation, BMP, IGF/PI3K, FGF or IHH signaling was inhibited up to day 14. All treatments significantly reduced proliferation > 50% and, thus, seemed to participate in the re-entry into the cell cycle. To study whether the same pathways are relevant to maintain cells in a proliferative state later on, inhibitors were supplemented from day 14–28. This resulted in a significant decrease of proliferation in the groups treated with inhibitors of BMP (67% decrease), FGF (70%) and IHH (30%) signaling, while inhibition of IGF/PI3K did not influence late proliferation. Although BMP-4, IGF-1 or FGF-18 are known mitogenic factors in the growth plate, stimulation of cells by exogenous addition of these factors did not enhance proliferation in any differentiation phase. In contrast, stimulation of IHH signaling from day 14–28 significantly increased proliferation by 44%. This is in line with the documented strong mitogenic activity of hedgehog signaling in the proliferative zone of the growth plate. Thus, our data demonstrated that BMP, IGF/PI3K, FGF and IHH essentially participate in the regulation of proliferation during in vitro chondrogenesis. Early or late activation of single pathways by exogenous factors was, however, not sufficient to increase proliferation significantly with the exception of late activation of hedgehog signaling.
Summary. Shear stress and hydrostatic effects on the hMSCs early mechano gene response were similar. For the same magnitude gene response, the hydrostatic compression (1.5×10. 5. Pascal) is a 200000 times greater than the force exerted by shear stress (0.7 Pascal). Introduction. In the lab, a perfusion bioreactor designed to automate the production of bone constructs was developed. The proof of concept was established in a large animal model of clinical relevance. The cells perfused in the bioreactor are likely to perceive 2 types of stresses: shear stress and hydrostatic pressure.