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The growing interest in regenerative medicine has opened new avenues for novel cell therapies using stem cells. Bone Marrow Aspirate (BMA) is an important source of stromal mesenchymal stem cells (MSCs). Conventional MSC harvesting from BMA relies on archaic centrifugation methods, often leading to poor yield due to osmotic stress, high centrifugation force, convoluted workflow, and long experimental time (∼ 2 – 3 hours). To address these issues, we have developed a scalable microfluidic technology based on Deterministic Lateral Displacement (DLD) for MSC isolation. This passive, label-free cell sorting method capitalizes on the morphological differences between MSCs and blood cells (leukocytes and RBCs) for effective separation using an inverted L-shaped pillar array. To improve throughput, we developed a novel portable multiplexed DLD system that can process 2.5 mL of raw BMA in 20 ± 5 minutes, achieving a 2-fold increase in MSC recovery compared to centrifugation methods. Taken together, we envision the developed DLD platform will enable fast and efficient isolation of MSCs from BMA for effective downstream cell therapy in clinical settings.

Introduction: C3 glomerulopathy (C3G) is an ultrarare, chronic and progressive nephropathy mediated by dysregulation of the alternative pathway of complement (AP), with poor prognosis and limited treatment options. Targeted inhibition of proximal AP through factor D (FD) blockade represents a rational treatment approach. We present two phase 2 proof-of-concept clinical studies of the orally active FD inhibitor danicopan in patients with C3G and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) (NCT03369236 and NCT03459443). Methods: A double-blind, placebo-controlled study in patients with C3G and a single-arm, open-label study in patients with C3G or IC-MPGN treated with danicopan are reported. The studies evaluated pharmacokinetic/pharmacodynamic (PK/PD), efficacy, and safety outcomes. The co-primary endpoints were change from baseline in composite biopsy score and the proportion of patients with a 30% reduction in proteinuria relative to baseline at 6 or 12 months. Results: Optimal systemic concentrations of danicopan were not achieved for complete and sustained inhibition of AP, although there was evidence that blockade of FD reduced AP activity shortly after drug administration. Consequently, limited clinical response was observed in key efficacy endpoints. While stable disease or improvement from baseline was seen in some patients, response was not consistent. The data confirmed the favorable safety profile of danicopan. Conclusion: While demonstrating a favorable safety profile, danicopan resulted in incomplete and inadequately sustained inhibition of AP, probably due to limitations in its PK/PD profile in C3G, leading to lack of efficacy. Complete and sustained AP inhibition is required for a clinical response in patients with C3G.

Background: Osteochondritis dissecans (OCD) occurs most commonly in the knees of young individuals. This condition is known to cause pain and discomfort in the knee and can lead to disability and early knee osteoarthritis. The cause is not well understood, and treatment plans are not well delineated. The Research in Osteochondritis Dissecans of the Knee (ROCK) group established a multicenter, prospective cohort to better understand this disease. Purpose: To provide a baseline report of the ROCK multicenter prospective cohort and present a descriptive analysis of baseline data for patient characteristics, lesion characteristics, and clinical findings of the first 1000 cases enrolled into the prospective cohort. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Patients were recruited from centers throughout the United States. Baseline data were obtained for patient characteristics, sports participation, patient-reported measures of functional capabilities and limitations, physical examination, diagnostic imaging results, and initial treatment plan. Descriptive statistics were completed for all outcomes of interest. Results: As of November 2020, a total of 27 orthopaedic surgeons from 17 institutions had enrolled 1004 knees with OCD, representing 903 patients (68.9% males; median age, 13.1 years; range, 6.3-25.4 years), into the prospective cohort. Lesions were located on the medial femoral condyle (66.2%), lateral femoral condyle (18.1%), trochlea (9.5%), patella (6.0%), and tibial plateau (0.2%). Most cases involved multisport athletes (68.1%), with the most common primary sport being basketball for males (27.3% of cases) and soccer for females (27.6% of cases). The median Pediatric International Knee Documentation Committee (Pedi-IKCD) score was 59.9 (IQR, 45.6-73.9), and the median Pediatric Functional Activity Brief Scale (Pedi-FABS) score was 21.0 (IQR, 5.0-28.0). Initial treatments were surgical intervention (55.4%) and activity restriction (44.0%). When surgery was performed, surgeons deemed the lesion to be stable at intraoperative assessment in 48.1% of cases. Conclusion: The multicenter ROCK group has been able to enroll the largest knee OCD cohort to date. This information is being used to further understand the pathology of OCD, including its cause, associated comorbidities, and initial presentation and symptoms. The cohort having been established is now being followed longitudinally to better define and elucidate the best treatment algorithms based on these presenting signs and symptoms.

Therapies using mesenchymal stromal cells (MSCs) to treat immune and inflammatory conditions are now at an exciting stage of development, with many MSC-based products progressing to phase II and III clinical trials. However, a major bottleneck in the clinical translation of allogeneic MSC therapies is the variable immunomodulatory properties of MSC products due to differences in their tissue source, donor heterogeneity and processes involved in manufacturing and banking. This variable functionality of MSC products likely contributes to the substantial inconsistency observed in the clinical outcomes of phase III trials of MSC therapies; several trials have failed to reach the primary efficacy endpoint. In this review, we discuss various strategies to consistently maintain or enhance the immunomodulatory potency of MSCs during ex vivo expansion, which will enable the manufacture of allogeneic MSC banks that have high potency and low variability. Biophysical and biochemical priming strategies, the use of culture additives such as heparan sulfates, and genetic modification can substantially enhance the immunomodulatory properties of MSCs during in vitro expansion. Furthermore, robust donor screening, the use of biomarkers to select for potent MSC subpopulations, and rigorous quality testing to improve the release criteria for MSC banks have the potential to reduce batch-to-batch heterogeneity and enhance the clinical efficacy of the final MSC product. Machine learning approaches to develop predictive models of individual patient response can enable personalized therapies and potentially establish correlations between in vitro potency measurements and clinical outcomes in human trials.

Supplemental material, sj-pdf-1-ajs-10.1177_03635465211057103 for Descriptive Epidemiology From the Research in Osteochondritis Dissecans of the Knee (ROCK) Prospective Cohort by Carl W. Nissen, Jay C. Albright, Christian N. Anderson, Michael T. Busch, Cathy Carlson, Sasha Carsen, Henry G. Chambers, Eric W. Edmonds, Jutta M. Ellermann, Henry B. Ellis, John B. Erickson, Peter D. Fabricant, Theodore J. Ganley, Daniel W. Green, Nathan L. Grimm, Benton E. Heyworth, James Hui Hoi Po, Mininder S. Kocher, Regina O. Kostyun, Aaron J. Krych, Kevin H. Latz, Dustin M. Loveland, Roger M. Lyon, Stephanie W. Mayer, Norbert M. Meenen, Matthew D. Milewski, Gregory D. Myer, Bradley J. Nelson, Jeffrey J. Nepple, Jie C. Nguyen, J. Lee Pace, Mark V. Paterno, Andrew T. Pennock, Crystal A. Perkins, John D. Polousky, Paul Saluan, Kevin G. Shea, Emily Shearier, Marc A. Tompkins, Eric J. Wall, Jennifer M. Weiss, S. Clifton Willimon, Philip L. Wilson, Rick W. Wright, Andrew M. Zbojniewicz and James L. Carey in The American Journal of Sports Medicine

© 2020 The Hong Kong Geriatrics Society and Hong Kong Association of Gerontology. Introduction. Delirium is a common complication of hip fracture that can be avoided or ameliorated by careful anticipatory case management. We aimed to investigate the incidence and risk factors of delirium in older patients with hip fracture treated in our structured integrated care unit, and to evaluate the impact of delirium on healthcare utilisation. Methods. We retrospectively reviewed records of patients aged ≥60 years and admitted to our unit from December 2014 to September 2018 with low-impact hip fracture. Our unit has implemented a structured integrated care programme based on the NICE guidelines. Primary outcome measure was the incidence of delirium. The diagnosis of delirium was established using the Confusion Assessment Method. Secondary outcome measures included length of hospital stay, readmission within 30 days of discharge, and mortality within 30 days and 1 year. Results. A total of 1304 patients were included and classified as non-delirium (349 men and 815 women; mean age, 79.2 years) and delirium (49 men and 91 women; mean age, 82.3 years). The overall within-episode incidence of delirium was thus 10.7%. Independent risk factors for delirium in older patients with hip fractures were age (odds ratio [OR]=1.028, p=0.02), surgical treatment (OR=2.202, p=0.006), dementia (OR=2.066, p=0.001), elevated body temperature (OR=1.966, p=0.001), urinary tract infection (OR=2.431, p