What is the Efficacy of Intra-Articular Platelet-Rich Plasma Injections for Knee Osteoarthritis in Clinical Practice? A "Real-Life" Prospective Cohort.

INTRODUCTION: Platelet-rich plasma (PRP) injections may improve symptoms in patients suffering from knee osteoarthritis. However, there is a lack of data on its effectiveness in a "real-life" cohort. This multi-site institutional registry study aimed to assess patients' longitudinal progress after PRP injection for knee osteoarthritis. MATERIALS AND METHODS: All patients receiving PRP injections for knee osteoarthritis at a large, integrated tertiary academic center (December 18, 2017 to March 1, 2021) were eligible. A prospective data collection instrument was used to collect patient demographics, procedural information, and patient-reported outcome measures. Overall, 97 patients met the inclusion criteria, and 53 were included in the analysis. RESULTS: One in four patients (26%) improved on all three Knee Injury and Osteoarthritis Outcome Score subscales: 17% in two subscales and 20% in one subscale, respectively. Overall, 64% of patients improved in at least one patient-reported outcomes measure. At six months post injection, 49% of patients were satisfied. CONCLUSION: PRP injection provides positive changes in two out of three patients in different magnitudes and characteristics with careful attention to clinically meaningful differences.

Cytocentric measurement for regenerative medicine.

Any Regenerative Medicine (RM) business requires reliably predictable cell and tissue products. Regulatory agencies expect control and documentation. However, laboratory tissue production is currently not predictable or well-controlled. Before conditions can be controlled to meet the needs of cells and tissues in culture for RM, we have to know what those needs are and be able to quantify them. Therefore, identification and measurement of critical cell quality attributes at a cellular or pericellular level is essential to generating reproducible cell and tissue products. Here, we identify some of the critical cell and process parameters for cell and tissue products as well as technologies available for sensing them. We also discuss available and needed technologies for monitoring both 2D and 3D cultures to manufacture reliable cell and tissue products for clinical and non-clinical use. As any industry matures, it improves and standardizes the quality of its products. Cytocentric measurement of cell and tissue quality attributes are needed for RM.

Automating iPSC generation to enable autologous photoreceptor cell replacement therapy.

BACKGROUND: Inherited retinal degeneration is a leading cause of incurable vision loss in the developed world. While autologous iPSC mediated photoreceptor cell replacement is theoretically possible, the lack of commercially available technologies designed to enable high throughput parallel production of patient specific therapeutics has hindered clinical translation. METHODS: In this study, we describe the use of the Cell X precision robotic cell culture platform to enable parallel production of clinical grade patient specific iPSCs. The Cell X is housed within an ISO Class 5 cGMP compliant closed aseptic isolator (Biospherix XVivo X2), where all procedures from fibroblast culture to iPSC generation, clonal expansion and retinal differentiation were performed. RESULTS: Patient iPSCs generated using the Cell X platform were determined to be pluripotent via score card analysis and genetically stable via karyotyping. As determined via immunostaining and confocal microscopy, iPSCs generated using the Cell X platform gave rise to retinal organoids that were indistinguishable from organoids derived from manually generated iPSCs. In addition, at 120 days post-differentiation, single-cell RNA sequencing analysis revealed that cells generated using the Cell X platform were comparable to those generated under manual conditions in a separate laboratory. CONCLUSION: We have successfully developed a robotic iPSC generation platform and standard operating procedures for production of high-quality photoreceptor precursor cells that are compatible with current good manufacturing practices. This system will enable clinical grade production of iPSCs for autologous retinal cell replacement.

Should an Age Cutoff Be Considered for Elective Total Knee Arthroplasty Patients? An Analysis of Operative Success Based on Patient-Reported Outcomes.

Total knee arthroplasty (TKA) is increasing in the elderly population; however, some patients, family members, and surgeons raise age-related concerns over expected improvement and risks. This study aimed to (1) evaluate the relationship between age and change in patient-reported outcome measures (PROMs); (2) model how many patients would be denied improvements in PROMs if hypothetical age cutoffs were implemented; and (3) assess length of stay (LOS), readmission, reoperation, and mortality per age group. A prospective cohort of 4,396 primary TKAs (August 2015-August 2018) was analyzed. One-year PROMs were evaluated via Knee injury and Osteoarthritis Outcome Score (KOOS)-pain, -physical function short form (-PS), and -quality of life (-QOL), as well as Veterans Rand-12 (VR-12) physical (-PCS) and mental component (-MCS) scores. Positive predictive values (PPVs) of the number of postoperative "failures" (i.e., unattained minimal clinically important difference in PROMs) relative to number of hypothetically denied "successes" from a theoretical age-group restriction was estimated. KOOS-PS and QOL median score improvements were equivalent among all age groups (p = 0.946 and p = 0.467, respectively). KOOS-pain improvement was equivalent for ≥80 and 60-69-year groups (44.4 [27.8-55.6]). Median VR-12 PCS improvements diminished as age increased (15.9, 14.8, and 13.4 for the 60-69, 70-79, and ≥80 groups, respectively; p = 0.002) while improvement in VR-12 MCS was similar among age groups (p = 0.440). PPV for failure was highest in the ≥80 group, yet remained <34% for all KOOS measures. Overall mortality was highest in the ≥80 group (2.14%, n = 9). LOS >2, non-home discharge, and 90-day readmission were highest in the ≥80 group (8.11% [n = 24], p < 0.001; 33.7% [n = 109], p < 0.001; and 34.4% [n = 111], p = 0.001, respectively). Elderly patients exhibited similar improvement in PROMs to younger counterparts despite higher LOS, non-home discharge, and 90-day readmission. Therefore, special care pathways should be implemented for those age groups.

Do patient-reported outcome measures improve after aseptic revision total hip arthroplasty?

BACKGROUND: The purpose of this study was to determine patient-reported outcome measures (PROMs) changes in: (1) pain, function and global health; and (2) predictors of PROMs in patients undergoing aseptic revision total hip arthroplasty (rTHA) using a multilevel model with patients nested within surgeon. METHODS: A prospective cohort of 216 patients with baseline and 1-year PROMs who underwent aseptic rTHA between January 2016 and December 2017 were analysed. The most common indication for rTHA was aseptic loosening, instability, and implant failure. The PROMs included in this study were HOOS Pain and HOOS Physical Function Short-form (PS), Veterans RAND-12 Physical Component Score (VR-12 PCS), and VR-12 Mental Component Score (MCS). Multivariable linear regression models were constructed for predicting 1-year PROMs. RESULTS: Mean 1-year PROMs improvement for aseptic revisions were 30.4 points for HOOS Pain and 22.1 points for HOOS PS. Predictors of better pain relief were patients with higher baseline pain scores. Predictors of better 1-year function were patients with higher baseline function and patients with a posterolateral hip surgical approach during revision. Although VR-12 PCS scores had an overall improvement, nearly 50% of patients saw no improvement or had worse physical component scores. Only 30.7% of patients reported improvements in VR-12 MCS. CONCLUSIONS: Overall, patients undergoing aseptic rTHA improved in pain and function PROMs at 1 year. Although global health assessment improved overall, nearly half of aseptic rTHA patients reported no change in physical/mental health status. The associations highlighted in this study can help guide the shared decision-making process by setting expectations before aseptic revision THA.

Regulatory and Ethical Aspects of Orthobiologic Therapies.

Orthobiologic therapies show significant promise to improve outcomes for patients with musculoskeletal pathology. There are considerable research efforts to develop strategies that seek to modulate the biological environment to promote tissue regeneration and healing and/or provide symptomatic relief. However, the regulatory pathways overseeing the clinical translation of these therapies are complex, with considerable worldwide variation. The introduction of novel biologic treatments into clinical practice raises several ethical dilemmas. In this review, we describe the process for seeking approval for biologic therapies in the United States, Europe, and Japan. We highlight a number of ethical issues raised by the clinical translation of these treatments, including the design of clinical trials, monitoring outcomes, biobanking, "off-label" use, engagement with the public, marketing of unproven therapies, and scientific integrity.

Improved biological performance of human cartilage-derived progenitors in platelet lysate xenofree media in comparison to fetal bovine serum media.

Primary articular cartilage-derived cells are among the preferred contenders for cell-based therapy approaches for cartilage repair. Limited access to primary human cartilage tissue necessitates the process of in vitro cell expansion to obtain sufficient cells for therapeutic purposes. Therapeutic outcomes of such cell-based approaches become highly dependent on the quality of the in vitro culture-expanded cells. The objective of this study was to determine the differential biological effects of human platelet lysate (hPL) xeno-free defined media vs FBS containing traditional media on primary human cartilage-derived cells. Our goal in pursuing this work was to identify a preferred xenofree media alternative, that can be used as a platform for expansion of cells intended for clinical applications. Primary cartilage-derived cells obtained from five patients were simultaneously cultured in two expansion media's: (1) traditional (DMEM+10%FBS+1%P/S) and (2) defined xenofree (Nutristem® complete media+0.5%hPL). Connective tissue progenitors (CTPs) were assayed by standard colony forming unit assay, morphology, proliferation in early and late passages, expression of MSC associated cell-surface markers (CD73, CD90 and CD105) and trilineage differentiation (adipogenesis, osteogenesis and chondrogenesis) were considered for comparison of biological performance. Early biological performance of primary cartilage-derived cells was significantly improved in Nutristem® expansion media in comparison to traditional expansion media with respect to (1) Colony forming efficiency tended to be higher (p = 0.058) and (2) CTPs formed larger colonies with respect to total cells per colony and colony area (p < 0.01). In the culture expanded cell population, Nutristem® expansion media was superior to traditional expansion media with respect to: (1) overall proliferation rate through passages 1-4 (p = 0.027), (2) total cells harvested at end of passage 4 (p = 0.028) and (3) total positive stain area of CD73 (p = 0.006), CD90 (p = 0.001) and CD105 (p = 0.049). Nutristem®-hPL expanded cells when differentiated in respective xenofree serum-free defined MSCgo™ differentiated media's, also showed significant improvement in adipogenic, osteogenic and chondrogenic marker expression. Overall, we convincingly demonstrated that a low concentration of hPL in combination with defined xenofree media is an effective and economic growth supplement to culture expand primary cartilage-derived cells. It can be manufactured under cGMP conditions to improve clinical-grade cell products' quality for therapeutic applications.

Assessment of Clinical, Tissue, and Cell-Level Metrics Identify Four Biologically Distinct Knee Osteoarthritis Patient Phenotypes.

OBJECTIVE: Clinical heterogeneity of primary osteoarthritis (OA) is a major challenge in understanding pathogenesis and development of targeted therapeutic strategies. This study aims to (1) identify OA patient subgroups phenotypes and (2) determine predictors of OA severity and cartilage-derived stem/progenitor concentration using clinical-, tissue-, and cell- level metrics. DESIGN: Cartilage, synovium (SYN) and infrapatellar fatpad (IPFP) were collected from 90 total knee arthroplasty patients. Clinical metrics (patient demographics, radiograph-based joint space width (JSW), Kellgren and Lawrence score (KL)), tissue metrics (cartilage histopathology grade, glycosaminoglycans (GAGs)) and cell-based metrics (cartilage-, SYN-, and IPFP-derived cell concentration ([Cell], cells/mg), connective tissue progenitor (CTP) prevalence (PCTP, CTPs/million cells plated), CTP concentration, [CTP], CTPs/mg)) were assessed using k-mean clustering and linear regression model. RESULTS: Four patient subgroups were identified. Clusters 1 and 2 comprised of younger, high body mass index (BMI) patients with healthier cartilage, where Cluster 1 had high CTP in cartilage, SYN, and IPFP, and Cluster 2 had low [CTP] in cartilage, SYN, and IPFP. Clusters 3 and 4 comprised of older, low BMI patients with diseased cartilage where Cluster 3 had low [CTP] in SYN, IPFP but high [CTP] in cartilage, and Cluster 4 had high [CTP] in SYN, IPFP but low [CTP] in cartilage. Age (r = 0.23, P = 0.026), JSW (r = 0.28, P = 0.007), KL (r = 0.26, P = 0.012), GAG/mg cartilage tissue (r = -0.31, P = 0.007), and SYN-derived [Cell] (r = 0.25, P = 0.049) were weak but significant predictors of OA severity. Cartilage-derived [Cell] (r = 0.38, P < 0.001) and PCTP (r = 0.9, P < 0.001) were moderate/strong predictors of cartilage-derived [CTP]. CONCLUSION: Initial findings suggests the presence of OA patient subgroups that could define opportunities for more targeted patient-specific approaches to prevention and treatment.

No clinically meaningful difference in 1-year patient-reported outcomes among major approaches for primary total hip arthroplasty.

BACKGROUND: Debate continues around the most effective surgical approach for primary total hip arthroplasty (THA). This study's purpose was to compare 1-year patient-reported outcome measures (PROMs) of patients who underwent direct anterior (DA), transgluteal anterolateral (AL)/direct lateral (DL), and posterolateral (PL) approaches. METHODS: A prospective consecutive series of primary THA for osteoarthritis (n = 2390) were performed at 5 sites within a single institution with standardised care pathways (20 surgeons). Patients were categorised by approach: DA (n = 913; 38%), AL/DL (n = 505; 21%), or PL (n = 972; 41%). Primary outcomes were pain, function, and activity assessed by 1-year postoperative PROMs. Multivariable regression modeling was used to control for differences among the groups. Wald tests were performed to test the significance of select patient factors and simultaneous 95% confidence intervals were constructed. RESULTS: At 1-year postoperative, PROMs were successfully collected from 1842 (77.1%) patients. Approach was a statistically significant factor for 1-year HOOS pain (p = 0.002). Approach was not a significant factor for 1-year HOOS-PS (p = 0.16) or 1-year UCLA activity (p = 0.382). Pairwise comparisons showed no significant difference in 1-year HOOS pain scores between DA and PL approach (p > 0.05). AL/DL approach had lower (worse) pain scores than DA or PL approaches with differences in adjusted median score of 3.47 and 2.43, respectively (p < 0.05). CONCLUSIONS: Patients receiving the AL/DL approach had a small statistical difference in pain scores at 1 year, but no clinically meaningful differences in pain, activity, or function exist at 1-year postoperative.

Biologic Association Annual Summit: 2020 Report.

Interest and research in biologic approaches for tissue healing are exponentially growing for a variety of musculoskeletal conditions. The recent hype concerning musculoskeletal biological therapies (including viscosupplementation, platelet-rich plasma, and cellular therapies, or "stem cells") is driven by several factors, including demand by patients promising regenerative evidence supported by substantial basic and translational work, as well as commercial endeavors that complicate the scientific and lay understanding of biological therapy outcomes. While significant improvements have been made in the field, further basic and preclinical research and well-designed randomized clinical trials are needed to better elucidate the optimal indications, processing techniques, delivery, and outcome assessment. Furthermore, biologic treatments may have potential devastating complications when proper methods or techniques are ignored. For these reasons, an association comprising several scientific societies, named the Biologic Association (BA), was created to foster coordinated efforts and speak with a unified voice, advocating for the responsible use of biologics in the musculoskeletal environment in clinical practice, spearheading the development of standards for treatment and outcomes assessment, and reporting on the safety and efficacy of biologic interventions. This article will introduce the BA and its purpose, provide a summary of the 2020 first annual Biologic Association Summit, and outline the future strategic plan for the BA.

A comprehensive dataset of histopathology images, grades and patient demographics for human Osteoarthritis Cartilage.

Osteoarthritis (OA) is a leading cause of disability in older adults and takes substantial toll at personal, economic and societal levels. There is inadequate comprehension of OA disease progression specifically during the early phases of OA. This knowledge is critical to understanding the heterogeneity in OA progression as well as enable development of targeted therapeutics at the start of the disease rather than end-stage. Histopathology of cartilage is a common method used to assess in situ state of cartilage tissue. The data presented in this article assesses the histopathological status of human cartilage specimens collected from 90 patients (n = 180). Each specimen was processed for histology and stained with hematoxylin and eosin (HE) and safranin O fast-green (SafO) for acquiring brightfield images to visualize changes in cartilage structure, cells, gycosaminoglycan content and tidemark integrity. The unstained sections were imaged using polarized light microscopy (PLM) to visualize changes in collagen organization and composition within the cartilage specimen. All the specimens were systematically graded by three scorers using established primary OA cartilage grading systems including Histological-Histochemical Grading System (HHGS), advanced Osteoarthritis Research Society International (OARSI) system and Polarized Light Microscopy (PLM) scoring system. These data can be used by the OA community as an educational resource to train new reviewers (scorers), it serves as a comprehensive image database for experienced OA community to review the wide spectrum of histopathological features presented by these mild to moderate OA specimens, to define different OA-subtypes, and to generate hypothesis on OA progression mechanisms. Finally, the high quality images can be used to develop machine learning algorithms for classification of OA, automated detection and segmentation of existing or new OA features that can serve as early OA histopathological indicators.

Patient Age and Cell Concentration Influence Prevalence and Concentration of Progenitors in Bone Marrow Aspirates: An Analysis of 436 Patients.

BACKGROUND: Connective tissue progenitors (CTPs) resident in native tissues serve as biological building blocks in tissue repair and remodeling processes. Methods for analysis and reporting on CTP quantity and quality are essential for defining optimal cell sources and donor characteristics and the impact of cell processing methods for cell therapy applications. The present study examines the influence of donor characteristics and cell concentration (nucleated cells/mL) on CTP prevalence (CTPs/million nucleated cells) and CTP concentration (CTPs/mL) in bone marrow aspirates (BMAs). METHODS: Iliac crest bone marrow was aspirated from 436 patients during elective total knee or hip arthroplasty. Bone marrow-derived nucleated cells were plated at a density of 1.19 × 105 cells/cm2. Colony-forming unit analysis was performed on day 6. RESULTS: Large variation was seen between donors. Age (p < 0.05) and cell concentration (p < 0.001) significantly influenced CTP prevalence and CTP concentration. For every 1-year increase in age, the odds of having at least an average CTP prevalence and CTP concentration decreased by 1.5% and 1.6%, respectively. For every 1 million cells/mL increase in cell concentration, the odds of having at least an average CTP prevalence and CTP concentration increased by 2.2% and 7.9%, respectively. Sex, race, body mass index (BMI), and the presence of osteoporosis did not influence CTP prevalence or CTP concentration. CONCLUSIONS: BMA-derived CTPs were obtained from all patient groups. CTP prevalence and CTP concentration decreased with age. Cell concentration decreased with age and positively correlated with total CTP prevalence and CTP concentration. The mean CTP concentration in patients >60 years of age was a third of the CTP concentration in patients <30 years of age. CLINICAL RELEVANCE: Proper BMA techniques are necessary to obtain a high-quality yield and composition of cells and CTPs. The reduced CTP concentration and CTP prevalence in the elderly may be mitigated by the use of cell processing methods that increase CTP concentration and CTP prevalence (e.g., by removing red blood cells, serum, and non-CTPs or by increasing aspirate volumes). Cell concentration in the BMA can be measured at the point of care and is an appropriate initial assessment of the quality of BMA.

Characterization of heterogeneous primary human cartilage-derived cell population using non-invasive live-cell phase-contrast time-lapse imaging.

Reliable and reproducible cell therapy strategies to treat osteoarthritis demand an improved characterization of the cell and heterogeneous cell population resident in native cartilage tissue. Using live-cell phase-contrast time-lapse imaging (PC-TLI), this study investigates the morphological attributes and biological performance of the three primary biological objects enzymatically isolated from primary human cartilage: connective tissue progenitors (CTPs), non-progenitors (NPs) and multi-cellular structures (MCSs). The authors' results demonstrated that CTPs were smaller in size in comparison to NPs (P < 0.001). NPs remained part of the adhered cell population throughout the cell culture period. Both NPs and CTP progeny on day 8 increased in size and decreased in circularity in comparison to their counterparts on day 1, although the percent change was considerably less in CTP progeny (P < 0.001). PC-TLI analyses indicated three colony types: single-CTP-derived (29%), multiple-CTP-derived (26%) and MCS-derived (45%), with large heterogeneity with respect to cell morphology, proliferation rate and cell density. On average, clonal (CL) (P = 0.009) and MCS (P = 0.001) colonies exhibited higher cell density (cells per colony area) than multi-clonal (MC) colonies; however, it is interesting to note that the behavior of CL (less cells per colony and less colony area) and MCS (high cells per colony and high colony area) colonies was quite different. Overall effective proliferation rate (EPR) of the CTPs that formed CL colonies was higher than the EPR of CTPs that formed MC colonies (P = 0.02), most likely due to CTPs with varying EPR that formed the MC colonies. Finally, the authors demonstrated that lag time before first cell division of a CTP (early attribute) could potentially help predict its proliferation rate long-term. Quantitative morphological characterization using non-invasive PC-TLI serves as a reliable and reproducible technique to understand cell heterogeneity. Size and circularity parameters can be used to distinguish CTP from NP populations. Morphological cell and colony features can also be used to reliably and reproducibly identify CTP subpopulations with preferred proliferation and differentiation potentials in an effort to improve cell manufacturing and therapeutic outcomes.

Influence of Glucose Concentration on Colony-Forming Efficiency and Biological Performance of Primary Human Tissue-Derived Progenitor Cells.

OBJECTIVE: Glucose concentrations used in current cell culture methods are a significant departure from physiological glucose levels. The study focuses on comparing the effects of glucose concentrations on primary human progenitors (connective tissue progenitors [CTPs]) used for cartilage repair. DESIGN: Cartilage- (Outerbridge grade 1, 2, 3; superficial and deep zone cartilage), infrapatellar fatpad-, synovium-, and periosteum-derived cells were obtained from 63 patients undergoing total knee arthroplasty and cultured simultaneously in fresh chondrogenic media containing 25 mM glucose (HGL) or 5 mM glucose (NGL) for pairwise comparison. Automated ASTM-based quantitative image analysis was used to determine colony-forming efficiency (CFE), effective proliferation rates (EPR), and sulfated-proteoglycan (GAG-ECM) staining of the CTPs across tissue sources. RESULTS: HGL resulted in increased cell cultures with CFE = 0 compared with NGL in all tissue sources (P = 0.049). The CFE in NGL was higher than HGL for superficial cartilage (P < 0.001), and contrary for synovium-derived CTPs (P = 0.046) when CFE > 0. EPR of the CTPs did not differ between the media in the 6-day assay time period (P = 0.082). The GAG-ECM area of the CTPs and their progeny was increased in presence of HGL (P = 0.027). CONCLUSION: Glucose concentration is critical to progenitor's physiology and should be taken into account in the setting of protocols for clinical or in vitro cell expansion strategies.

The Potential Effects of Imposing a Body Mass Index Threshold on Patient-Reported Outcomes After Total Knee Arthroplasty.

BACKGROUND: Operative eligibility thresholds based on body mass index (BMI) alone may risk restricting access to improved pain control, function, and quality of life. This study evaluated the use of BMI-cutoffs to offering TKA in avoiding: 1) 90-day readmission, 2) one-year mortality, and 3) failure to achieve clinically important one-year PROMS improvement (MCID). METHODS: A total of 4126 primary elective unilateral TKA patients from 2015 to 2018 were prospectively collected. For specific BMI(kg/m2) cutoffs: 30, 35, 40, 45, and 50, the positive predictive value (PPV) for 90-day readmission, one-year mortality, and failure to achieve one-year MCID were calculated. The number of patients denied complication-free postoperative courses per averted adverse outcome/failed improvement was estimated. RESULTS: Rates of 90-day readmission and one-year mortality were similar across BMI categories (P > .05, each). PPVs for preventing 90-day readmission and one-year mortality were low across all models of BMI cutoffs. The highest PPV for 90-day readmission and one-year mortality was detected at cutoffs of 45 (6.4%) and 40 (0.87%), respectively. BMI cutoff of 40 would deny 18 patients 90-day readmission-free, and 194 patients one-year mortality-free postoperative courses for each averted 90-day readmission/one-year mortality. Such cutoff would also deny 11 patients an MCID per avoided failure. Implementing BMI thresholds alone did not influence the rate of improvements in KOOS-PS, KRQOL, or VR-12. CONCLUSION: Utilizing BMI cutoffs as the sole determinants of TKA ineligibility may deny patients complication-free postoperative courses and clinically important improvements. Shared decision-making supported by predictive tools may aid in balancing the potential benefit TKA offers to obese patients with the potentially increased complication risk and cost of care provision.

Automated in-process characterization and selection of cell-clones for quality and efficient cell manufacturing.

Delivery of safe, effective and reliable cellular therapies, whether based on mesenchymal stromal cells (MSCs) or induced pluripotent stem cells (iPSCs), demand standardization of cell culture protocols. There is a need to develop automation platform that enables the users to generate culture expanded human cell populations that improves the quality and reduces batch-to-batch variation with respect to biological potential. Cell X™ robot was designed to address these current challenges in the cell fabrication industry. It utilizes non-invasive large field of view quantitative image analysis to guide an automated process of targeted "biopsy" (cells or media), "picking" (selection) of desired cells or colonies, or "weeding" (removal) of undesired cells, thus providing an unprecedented ability to acquire quantitative measurement in a complex heterogeneous cell environment "in process" and then to act on those measurements to define highly reproducible methods for cell and colony "management" based on application specific critical quality attributes to improve the quality of the manufactured cell lines and cell products.

The Cost-Effectiveness of Platelet-Rich Plasma Injections for Knee Osteoarthritis: A Markov Decision Analysis.

BACKGROUND: Use of platelet-rich-plasma (PRP) injections for treating knee osteoarthritis has increased over the past decade. We used cost-effectiveness analysis to evaluate the value of PRP in delaying the need for total knee arthroplasty (TKA). METHODS: We developed a Markov model to analyze the baseline case: a 55-year-old patient with Kellgren-Lawrence grade-II or III knee osteoarthritis undergoing a series of 3 PRP injections with a 1-year delay to TKA versus a TKA from the outset. Both health-care payer and societal perspectives were included. Transition probabilities were derived from systematic review of 72 studies, quality-of-life (QOL) values from the Tufts University Cost-Effectiveness Analysis Registry, and individual costs from Medicare reimbursement schedules. Primary outcome measures were total costs and quality-adjusted life years (QALYs), organized into incremental cost-effectiveness ratios (ICERs) and evaluated against willingness-to-pay thresholds of $50,000 and $100,000. One and 2-way sensitivity analyses were performed as well as a probabilistic analysis varying PRP-injection cost, TKA delay intervals, and TKA outcomes over 10,000 different simulations. RESULTS: From a health-care payer perspective, PRP resulted in 14.55 QALYs compared with 14.63 for TKA from the outset, with total health-care costs of $26,619 and $26,235, respectively. TKA from the outset produced a higher number of QALYs at a lower cost, so it dominated. From a societal perspective, PRP cost $49,090 versus $49,424 for TKA from the outset. The ICER for TKA from the outset was $4,175 per QALY, below the $50,000 willingness-to-pay threshold. Assuming the $728 published cost of a PRP injection, no delay time that was <10 years produced a cost-effective course. When the QOL value was increased from the published value of 0.788 to >0.89, PRP therapy was cost-effective with even a 1-year delay to TKA. CONCLUSIONS: When considering direct and unpaid indirect costs, PRP injections are not cost-effective. The primary factor preventing PRP from being cost-effective is not the price per injection but rather a lack of established clinical efficacy in relieving pain and improving function and in delaying TKA. PRP may have value for higher-risk patients with high perioperative complication rates, higher TKA revision rates, or poorer postoperative outcomes. LEVEL OF EVIDENCE: Economic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The effect of body mass index on 30-day complications after total hip arthroplasty.

BACKGROUND: Evaluating body mass index (BMI) as a continuous variable eliminates the potential pitfalls of only considering BMI as a binary or categorical variable, as most studies do when correlating BMI and total hip arthroplasty (THA) outcomes. Therefore, the objective of this study was to correlate the effect of continuous BMI on 30-day complications post-THA. Specifically, we correlated BMI to: (1) 30-day readmissions and reoperations; (2) medical complications; and (3) surgical complications in: (a) normal-weight; (b) over-weight; (c) obese; and (d) morbidly obese patients. METHODS: Using the NSQIP database, 93,598 primary THAs were identified. 30-day rates of readmissions, reoperations, and medical/surgical complications as well as patient BMI data were extrapolated. A comparative analysis using univariate, multivariate, and spline regression models adjusting for demographics and comorbidities were created to study the continuous effect of BMI on different outcomes. RESULTS: Readmission (p < 0.001), reoperation (p = 0.007), superficial infection (p = 0.003), prosthetic joint infection (p < 0.001), and sepsis (p = 0.026) had a J-shaped relationship with BMI, with the lowest rates seen in patients with BMI around 28 kg/m2. The risks of mortality (p = 0.007) and transfusion (p < 0.001) had a reverse J-shaped relationship, with the risk steadily decreasing for BMIs in the normal weight and overweight range, and then flattening afterwards. CONCLUSION: This data proposes a multifactorial effect of BMI on post-THA complications. Considering BMI as a continuous variable allows for a better assessment when considering the interplay between modifiable risk factors, such as smoking or alcohol use, as well as multiple comorbidities.

Native-Osteoarthritic Joint Resident Stem and Progenitor Cells for Cartilage Cell-Based Therapies: A Quantitative Comparison With Respect to Concentration and Biological Performance.

BACKGROUND: Cell-based therapy for cartilage repair is a promising approach and is becoming an established technique. Yet, there is no consensus on the optimal cell source. PURPOSE: To provide a donor-matched quantitative comparison of the connective tissue progenitors (CTPs) derived from cartilage (Outerbridge grade 1-3 [G1-2-3]), bone marrow aspirate concentrate (BMC), infrapatellar fat pad (IPFP), synovium, and periosteum with respect to (1) cell concentration ([Cell], cells/mL), (2) CTP prevalence (PCTP, colonies per million cells), and (3) biological performance based on in vitro proliferation potential (cells per colony) colony density, and differentiation potential (expression of negatively charged extracellular matrix: glycosaminoglycan-rich extra cellular matrix [GAG-ECM]). STUDY DESIGN: Descriptive laboratory study. METHODS: Tissues were obtained from 10 patients undergoing total knee arthroplasty (mean age, 59 years; women, n = 6). Automated quantitative colony-forming unit analysis was used to compare [Cell], PCTP, and CTP biological performance across tissue sources. RESULTS: [Cell] was highest in grade 3 cartilage (P = .002) and BMC (P = .001). Median PCTP was highest in IPFP (P = .001), synovium (P = .003), and G1-2 cartilage (P = .02). Proliferation was highest in synovium-derived CTPs (P < .001). Median colony density was highest in G1-2-3 (P < .001). Median GAG-ECM was highest in G1-2-3 (P < .001). Within each patient, CTPs derived from all tissues were highly heterogeneous in biological performance as determined by cells per colony, density, and GAG-ECM. CONCLUSION: Tissue sources differ in [Cell], PCTP, and biological attributes. The data presented in this study suggest that cartilage (G1-2-3) is the preferred tissue source for cartilage repair based on PCTP and GAG-ECM, followed by synovium, IPFP, BMC, and periosteum. However, due to the heterogeneous mixture of CTPs within each tissue source, there exists a subset of CTPs with biological performance similar to G1-2-3 cartilage, particularly in synovium and IPFP. Performance-based clonal selection and expansion of preferred CTPs and their progeny will potentially lead to improved cell population with predictive future. CLINICAL RELEVANCE: Optimal tissue regeneration strategies will require informed decisions regarding which of the available tissue sources to use. Optimizing cell sourcing in any tissue may require separation of CTPs with preferred attributes from those with less desirable attributes. The heterogeneity manifest in the early stage of colony formation represents an opportunity for performance-based clone selection for clinical cell processing and manufacturing.