The Efficacy of Platelet-Rich Plasma for Improving Pain and Function in Lateral Epicondylitis: A Systematic Review and Meta-analysis with Risk-of-Bias Assessment.

PURPOSE: To assess the efficacy of platelet-rich plasma (PRP) for lateral epicondylitis and evaluate its impact on pain and functional outcomes. METHODS: This study followed Preferred Reporting Items and Systematic Reviews and Meta-Analyses guidelines. A comprehensive literature search was conducted in September 2019 and repeated in April 2020 using electronic databases PubMed, MEDLINE, and the Cochrane Library. Baseline and 3-, 6-, and 12-month data were extracted for visual analog scale (VAS), Disabilities of the Arm, Shoulder, and Hand (DASH), and modified Mayo Clinic performance index for the elbow (MAYO) scores. Only level 1 studies with patients who had not undergone surgery were included. Outcomes data, study design, demographic variables, PRP formulation, and comparator treatments were recorded. Statistical analyses of pooled weighted mean differences (WMDs) were performed and compared with estimated minimal clinically important difference (MCID) values. The Coleman Methodology Score (CMS) was used to assess methodological quality, and the Cochrane risk-of-bias assessment was performed. RESULTS: This review included 16 level I studies, 9 of which (581 total patients, 281 receiving single injections of PRP) were quantitatively analyzed. The average age was 41.5 years, 56.8% of patients were female, and mean follow-up was 7.5 months. The mean CMS was 78.94 ± 12.74 (range 59 to 97), and 5 of 16 studies were at low risk for bias. Patients who received PRP had significantly improved VAS scores at 3 months (WMD -0.85; 95% confidence interval [CI] -1.03, -0.66; P < .01) and 6 months (WMD -0.74; 95% CI -0.98, -0.50; P < .01) compared with those who received autologous whole blood, though MAYO scores were statistically equivalent. Comparing PRP to corticosteroids, VAS and DASH scores were not significantly different at 3 months, although PRP was superior at 6 months for VAS (WMD -1.70; 95% CI -2.65, -0.75; P < .01) and DASH (WMD -6.23; 95% CI -10.78, -1.69; P < .01). Most differences in VAS and DASH scores exceeded the 5% absolute difference estimate for their respective MCIDs but fell short of the 10% estimate. CONCLUSION: Considering the small number of comparable studies, lack of quantification of specific PRP content, considerable heterogeneity between randomized control trials, and most effect sizes being equivocal within the framework of 2 estimated MCID values, the authors can neither scientifically support nor discourage the usage of PRP for lateral epicondylitis despite finding statistically significant improvements in pain and functional outcomes. LEVEL OF EVIDENCE: I, prognostic.

Governmental Regulations and Increasing Food and Drug Administration Oversight of Regenerative Medicine Products: What's New in 2020?

The United States Food and Drug Administration (FDA) is responsible for protecting and promoting public health through rules and regulations. Over the past few years, the field of regenerative medicine and cell therapy have garnered significant interest, and this evolving new biology is changing fast and challenging regulatory bodies. The FDA has published a series of guidance documents outlining steps to protect consumers against potentially dangerous and unproven treatments. The agency has offered a grace period for "stem cell clinics" until November 2020 to come into compliance by obtaining Investigational New Drug applications and working to secure premarket approval of their products. With the documentation of hundreds of "stem cell clinics," the FDA needs to enforce the adherence to their outlined standards to protect patients. The aim of this review was to provide an overview of these FDA regulations and some current issues within the industry. The purpose is to educate and inform the musculoskeletal community about the current government regulations of this new expanding biology. LEVEL OF EVIDENCE: Level V, expert opinion.

Repair of Rotator Cuff Tendon Defects in Aged Rats Using a Growth Factor Injectable Gel Scaffold.

PURPOSE: To determine if the tendon-specific crosslinking gelatin (Col-Tgel) impregnated with growth factors promotes tendon healing at the bone interface and in a tendon window model. METHODS: Two different Col-Tgel formulations were first tested in vitro by evaluating cell morphology and tendogenic differentiation. After the optimum formulation was determined, the gel was mixed with either transforming growth factor-ß3 (TGF-ß3) or growth differentiation factor-7 (GDF-7) growth factor and prepared for injections. Window defects were induced in 12 animals, which were randomized into the following treatments: (1) sham, (2) empty Col-Tgel, (3) Col-Tgel containing TGF-ß3, or (4) Col-Tgel containing GDF-7. Based on these results, the sham, empty Col-Tgel, and Col-Tgel containing TGF-ß3 were applied to the supraspinatus repair interface. Tendons were analyzed biomechanically and histologically using hematoxylin and eosin and Masson's trichrome staining. RESULTS: In the window defect model, histologic scores were the best in rats treated with TGF-ß3 containing Col-Tgel, followed by the empty Col-Tgel scaffold, and finally the sham control. The GDF-7 Col-Tgel was not further tested because occasional ectopic cartilage and bone formation was found in the prior window defect model. In the supraspinatus repair model, there was no statistical difference (P > .05) in the biomechanical strength among the 3 treatment groups, but load-to-failure ratio improved when TGF-ß3 was added to the scaffold, suggesting improved tendon healing. CONCLUSIONS: This pilot study evaluated the performance of an injectable gel tendon graft in a population of retired breeder rats. The results suggest that Col-Tgel containing TGF-ß3 may be a useful adjunctive treatment for surgical repair of full-thickness rotator cuff tears. Histologic and biomechanical scores suggest that Col-Tgel containing TGF-ß3 promotes tendon healing. CLINICAL RELEVANCE: The results of this study suggest that shoulders injected with Col-Tgel may be a useful adjunctive treatment for repair of rotator cuff tears.

Minimal clinically important difference (MCID) for patient-reported shoulder outcomes.

BACKGROUND: The minimal clinically important difference (MCID) is used when interpreting the importance of outcome data. However, a consensus regarding the MCID for commonly used patient-reported outcomes in shoulder surgery has not been established. The purpose of this systematic review was to evaluate the available literature on shoulder MCID to improve clinical interpretation of shoulder outcome data. METHODS: A systematic review of the literature was conducted to identify studies reporting anchor-based MCID values for the patient-reported outcomes recommended by the American Shoulder and Elbow Surgeons (ASES): Veterans Rand 12 score, ASES score, Single Assessment Numeric Evaluation (SANE) score, Western Ontario Rotator Cuff (WORC) score, Western Ontario Osteoarthritis Score (WOOS), Western Ontario Shoulder Instability Index (WOSI), Pennsylvania Shoulder Score, and Oxford Shoulder Score (OSS). RESULTS: A total of 14 articles reporting anchor-based MCID values were included in the final analysis. No studies reporting the Western Ontario Osteoarthritis Score (WOOS) were identified. The ASES score (6 studies), OSS (4 studies), and WORC score (2 studies) were the only instruments investigated in more than 1 study. The average reported MCID values for the ASES, OSS, and WORC scores were 15.5 (15% total difference), 275.7 (13% total difference), and 6 (13% total difference), respectively. The vast majority of studies failed to report information necessary to validate the credibility of these MCID values. DISCUSSION AND CONCLUSION: The current utility of the MCID for patient-report shoulder outcome instruments is limited by poor study methodology, inadequate reporting, and a lack of data. Further research is needed to more clearly define the MCID values for commonly used patient-reported outcomes in shoulder surgery.

Editorial Commentary: Injected Stem Cells May Not Adhere to Rabbit Cartilage Defects-Adherence May Be Improved Using Direct Application Techniques or Scaffolds.

Adipose-derived stem cells may adhere when properly applied to a cartilage defect in rabbits, whereas injected stem cells may not adhere. Stem cell harvesting, isolation, quantification, typing, and expansion are specific; complex cartilage regeneration remains unproven; and translation to a human model is enigmatic.

Injections Prior to Rotator Cuff Repair Are Associated With Increased Rotator Cuff Revision Rates.

PURPOSE: To determine whether shoulder injections prior to rotator cuff repair (RCR) are associated with deleterious surgical outcomes. METHODS: Two large national insurance databases were used to identify a total of 22,156 patients who received ipsilateral shoulder injections prior to RCR. They were age, sex, obesity, smoking status, and comorbidity matched to a control group of patients who underwent RCR without prior injections. The 2 groups were compared regarding RCR revision rates. RESULTS: Patients who received injections prior to RCR were more likely to undergo RCR revision than matched controls (odds ratio [OR], 1.52; 95% confidence interval [CI], 1.38-1.68; P < .0001). Patients who received injections closer to the time of index RCR were more likely to undergo revision (P < .0001). Patients who received a single injection prior to RCR had a higher likelihood of revision (OR, 1.25; 95% CI, 1.10-1.43; P = .001). Patients who received 2 or more injections prior to RCR had a greater than 2-fold odds of revision (combined OR, 2.12; 95% CI, 1.82-2.47; P < .0001) versus the control group. CONCLUSIONS: This study strongly suggests a correlation between preoperative shoulder injections and revision RCR. There is also a frequency dependence and time dependence to this finding, with more frequent injections and with administration of injections closer to the time of surgery both independently associated with higher revision RCR rates. Presently, on the basis of this retrospective database study, orthopaedic surgeons should exercise due caution regarding shoulder injections in patients whom they are considering to be surgical candidates for RCR. LEVEL OF EVIDENCE: Level III, therapeutic study.

Cutibacterium acnes persists despite topical clindamycin and benzoyl peroxide.

BACKGROUND: Cutibacterium (formerly Propionibacterium) acnes persists in the dermis despite standard skin antiseptic agents, prompting some surgeons to use topical antimicrobials such as benzoyl peroxide and clindamycin prior to shoulder arthroplasty surgery. However, the efficacy of these topical agents has not been established. METHODS: The upper backs of 12 volunteers were randomized into 4 treatment quadrants: topical benzoyl peroxide, topical clindamycin, combination topical benzoyl peroxide and clindamycin, and a negative control. The corresponding topical agents were applied to each site twice daily for 3 days. A 3-mm dermal punch biopsy specimen was obtained from each site and cultured for 14 days to assess for C acnes growth. Positive cultures were assessed for the hemolytic phenotype. The McNemar test was used to compare the proportion of positive cultures in each group. RESULTS: C acnes grew in 4 of 12 control sites (33.3%), 1 of 12 benzoyl peroxide sites (8.3%), 2 of 12 clindamycin sites (16.7%), and 2 of 12 combination benzoyl peroxide-clindamycin sites (16.7%). The C acnes hemolytic phenotype was present in 2 of 12 control specimens (16.7%) compared with 0 (0.0%) in the benzoyl peroxide group, 2 of 12 (16.7%) in the clindamycin group, and 2 of 12 (16.7%) in the combination benzoyl peroxide-clindamycin group. There were no statistically significant differences between treatment arms. CONCLUSION: The topical application of benzoyl peroxide and clindamycin did not eradicate C acnes in all subjects. The clinical implications of these findings are yet to be determined.

Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair.

OBJECTIVE: Human adult articular cartilage (AC) has little capacity for repair, and joint surface injuries often result in osteoarthritis (OA), characterised by loss of matrix, hypertrophy and chondrocyte apoptosis. Inflammation mediated by interleukin (IL)-6 family cytokines has been identified as a critical driver of proarthritic changes in mouse and human joints, resulting in a feed-forward process driving expression of matrix degrading enzymes and IL-6 itself. Here we show that signalling through glycoprotein 130 (gp130), the common receptor for IL-6 family cytokines, can have both context-specific and cytokine-specific effects on articular chondrocytes and that a small molecule gp130 modulator can bias signalling towards anti-inflammatory and antidegenerative outputs. METHODS: High throughput screening of 170 000 compounds identified a small molecule gp130 modulator termed regulator of cartilage growth and differentiation (RCGD 423) that promotes atypical homodimeric signalling in the absence of cytokine ligands, driving transient increases in MYC and pSTAT3 while suppressing oncostatin M- and IL-6-mediated activation of ERK and NF-κB via direct competition for gp130 occupancy. RESULTS: This small molecule increased proliferation while reducing apoptosis and hypertrophic responses in adult chondrocytes in vitro. In a rat partial meniscectomy model, RCGD 423 greatly reduced chondrocyte hypertrophy, loss and degeneration while increasing chondrocyte proliferation beyond that observed in response to injury. Moreover, RCGD 423 improved cartilage healing in a rat full-thickness osteochondral defect model, increasing proliferation of mesenchymal cells in the defect and also inhibiting breakdown of cartilage matrix in de novo generated cartilage. CONCLUSION: These results identify a novel strategy for AC remediation via small molecule-mediated modulation of gp130 signalling.

Propionibacterium Acnes Persists Despite Various Skin Preparation Techniques.

PURPOSE: To investigate the efficacy of various skin preparations at eradicating Propionibacterium acnes in the dermal layer of the skin. METHODS: Twelve healthy volunteers consented to participate in this study. Each subject's upper back was prepped using 4 different techniques: an isopropyl alcohol control, chlorhexidine gluconate paint, chlorhexidine gluconate plus a mechanical scrub, and a high-concentration chlorhexidine gluconate plus a mechanical scrub. A 3-mm dermal punch biopsy specimen was obtained at each preparation site. The 4 punch biopsy specimens were cultured for 14 days to assess for P. acnes growth. A Fisher's exact test was used to compare the proportion of positive cultures in each group and across biopsy sites. A Skillings-Mack test was used to compare the degree of culture positivity between the treatment arms. RESULTS: There were no reported complications in any of our subjects. P. acnes grew in 7 of the 12 control sites, 5 of the 12 chlorhexidine gluconate sites, 6 of the 12 chlorhexidine plus mechanical scrub sites, and 6 of the 12 high-concentration chlorhexidine gluconate plus mechanical scrub sites. There were no statistically significant differences between any of the treatment arms (P = .820). CONCLUSIONS: P. acnes persisted despite a variety of clinically relevant skin antisepsis preparations and techniques. LEVEL OF EVIDENCE: Level II, prospective comparative study.

Initial Characterization of Osteoblast Differentiation and Loss of RUNX2 Stability in the Newly Established SK11 Human Embryonic Stem Cell-Derived Cell Line.

We describe a novel model for investigation of genetically normal human osteoblasts in culture. SK11 is a clonal progenitor cell line derived from human embryonic stem cells. Initially selected based on the expression of chondrogenic markers when differentiated in micromass culture, SK11 cells display typical mRNA expression patterns of bone phenotypic genes under osteogenic conditions. These include osterix, α1(I) collagen, alkaline phosphatase, osteonectin, osteopontin, and osteocalcin. Similar to well-characterized murine osteoblast cultures, the osteoblast master regulator RUNX2 was present during the first few days after plating, but the protein disappeared during the first week of culture. Loss of RUNX2 expression is considered an important regulatory feature for osteoblast maturation. Indeed, following ∼2 weeks of differentiation, SK11 cultures exhibited robust calcium deposition, evidenced by alizarin red staining. We also introduced a lentiviral vector encoding doxycycline (dox)-inducible FLAG-tagged RUNX2 into SK11 cells. Dox-mediated enhancement of RUNX2 expression resulted in accelerated mineralization, which was further increased by co-treatment with BMP-2. Like the endogenous RUNX2, expression of the virally coded FLAG-RUNX2 was lost during the first week of culture despite persistent dox treatment. By following RUNX2 decay after dox withdrawal from day-5 versus day-3 cultures, we demonstrated a developmentally regulated decrease in RUNX2 stability. Availability of culture models for molecular investigation of genetically normal human osteoblasts is important because differences between murine and human osteoblasts, demonstrated here by the regulation of matrix Gla Protein, may have significant biomedical implications.

Umbilical Cord Tissue Offers the Greatest Number of Harvestable Mesenchymal Stem Cells for Research and Clinical Application: A Literature Review of Different Harvest Sites.

PURPOSE: Recent years have seen dramatic increases in the techniques used to harvest and isolate human mesenchymal stem cells. As the potential therapeutic aspects of these cells further develop, informative data on the differences in yields between tissue harvest sites and methods will become increasingly valuable. We collected and compared data on cell yields from multiple tissue harvest sites to provide insight into the varying levels of mesenchymal stem cells by tissue and offer primary and alternative tissue types for harvest and clinical application. METHODS: The PubMed and Medline databases were searched for articles relating to the harvest, isolation, and quantification of human mesenchymal stem cells. Selected articles were analyzed for relevant data, which were categorized according to tissue site and, if possible, standardized to facilitate comparison between sites. RESULTS: Human mesenchymal stem cell levels in tissue varied widely according to tissue site and harvest method. Yields for adipose tissue ranged from 4,737 cells/mL of tissue to 1,550,000 cells/mL of tissue. Yields for bone marrow ranged from 1 to 30 cells/mL to 317,400 cells/mL. Yields for umbilical cord tissue ranged from 10,000 cells/mL to 4,700,000 cells/cm of umbilical cord. Secondary tissue harvest sites such as placental tissue and synovium yielded results ranging from 1,000 cells/mL to 30,000 cells/mL. CONCLUSIONS: Variations in allogeneic mesenchymal stem cell harvest levels from human tissues reflect the evolving nature of the field, patient demographic characteristics, and differences in harvest and isolation techniques. At present, Wharton's jelly tissue yields the highest concentration of allogeneic mesenchymal stem cells whereas adipose tissue yields the highest levels of autologous mesenchymal stem cells per milliliter of tissue. CLINICAL RELEVANCE: This comparison of stem cell levels from the literature offers a primer and guide for harvesting mesenchymal stem cells. Larger mesenchymal stem cell yields are more desirable for research and clinical application.

Biomechanical comparison between the trapezius transfer and latissimus transfer for irreparable posterosuperior rotator cuff tears.

BACKGROUND: The purpose of this study was to characterize the biomechanical effects of the lower trapezius transfer and to compare it with the latissimus dorsi transfer in a cadaveric model of a massive posterosuperior rotator cuff tear. METHODS: Eight cadaveric shoulders were tested at 0°, 30°, and 60° of shoulder abduction. Range of motion, humeral rotational position due to muscle loading, joint reaction forces, and kinematics were measured. All specimens were tested in 4 conditions: intact, massive posterosuperior cuff tear, lower trapezius transfer, and latissimus dorsi transfer. A repeated-measures analysis of variance was used for statistical analysis. RESULTS: Internal rotation due to muscle loading increased with massive cuff tear compared with the intact condition (P < .05). The latissimus transfer corrected this change at 0° abduction, whereas the trapezius transfer corrected this at all abduction angles. The massive cuff tear decreased glenohumeral joint compression forces at all abduction angles; these forces were restored by the lower trapezius transfer (P < .05). At maximum humeral internal rotation and 0° of abduction, the humeral head apex shifted superiorly and laterally with massive cuff tear (P < .05); this shift was more closely restored to intact values by the trapezius transfer compared with the latissimus transfer (P < .05). CONCLUSION: The lower trapezius transfer is superior to the latissimus transfer at restoring native glenohumeral kinematics and joint reaction forces in our cadaveric model. It may be a promising treatment option for patients with a massive irreparable rotator cuff tear.

High resolution MRI evaluation of meniscal volume and anthropometric correlations.

The purpose of this study was to digitally determine meniscal volumes, and compare them with linear and surface area anthropometric measurements to evaluate these measurements for meniscal allograft sizing. Eighteen subjects (10 male and 8 female; mean age 37.5 years) underwent 3.0 T knee magnetic resonance imaging (MRI) of the dominant leg. The following morphometric measurements were evaluated: medial meniscal volume (MMV), lateral meniscal volume (LMV), tibial plateau width (TPW), width of the femoral condyles (WFC), and tibial plateau surface area (TPSA). MMV and LMV were compared to TPW, WFC, and TPSA. Meniscal volume and TPW were correlated to height and body-mass index (BMI) and stratified by gender. Statistical analysis included coefficient of determination (r(2)) between MRI-based MMV, LMV, TPW, TPSA, WFC, height, BMI, and gender. Significance was set at the P = 0.05 level. The mean MMV was 2275 mm(3) and the mean LMV was 2102 mm(3). TPW correlated well with meniscal volumes (r(2) > 0.62). WFC and TPSA correlated with meniscal volumes in the range of 0.40 < r(2) < 0.61. Height, BMI, and gender correlated poorly with total meniscal volume and TPW with values of r(2) < 0.44. Medial and lateral menisci have statistically similar volumes. TPW had the greatest utility for volumetric meniscal sizing. MRI-based TPW can be considered as a statistically accurate measurement for determining meniscal volumes and meniscal size.

Aseptically processed and chemically sterilized BTB allografts for anterior cruciate ligament reconstruction: a prospective randomized study.

PURPOSE: To compare the clinical outcomes of bone-patellar tendon-bone (BTB) allografts processed via a novel sterilization system with the traditional aseptically processed BTB allografts for anterior cruciate ligament (ACL) reconstruction. METHODS: A total of 67 patients undergoing ACL reconstruction at 6 independent investigation sites were randomized into one of two intervention groups, BioCleanse-sterilized or aseptic BTB allografts. Inclusion criteria included an acute, isolated, unilateral ACL tear, and exclusion criteria included prior ACL injury, multi-ligament reconstruction, and signs of degenerative joint disease. Post-op examiners and patients were blinded to graft type. Patients were evaluated at 6, 12, and 24 months. Clinical outcomes were compared using the IKDC, a KT-1000 knee arthrometer, level of effusion, and ranges of motion (ROM). RESULTS: After randomization, 24 patients received aseptic BTB allografts and 43 patients received BioCleanse-sterilized allografts. Significant improvement in IKDC scores (P < 0.0001) as well as KT-1000 results (P < 0.0001) was noted over the 24-month period for both groups. IKDC or KT-1000 results were not significantly different between groups at any time point. Active flexion ROM significantly improved from pre-op to 24-month follow-up (P < 0.0001) with no difference between groups at any time point. Active extension ROM did not differ significantly between the two groups. CONCLUSIONS: These results indicate that the sterilization process, BioCleanse, did not demonstrate a statistical difference in clinical outcomes for the BTB allograft at 2 years. The BioCleanse process may provide surgeons with allografts clinically similar to aseptically processed allograft tissue with the benefit of addressing donor-to-recipient disease. LEVEL OF EVIDENCE: II.

Cruciate ligament avulsion fractures: anatomy, biomechanics, injury patterns, and approach to management.

Injury to the ACL or PCL of the knee most commonly involves a tear of the collagenous fibers of the ligament. Less frequently, a cruciate ligament injury involves an avulsion fracture at the origin or insertion of the ligament, usually from the insertion site on the tibial surface. Avulsion fractures of the cruciate ligaments are important, as they can be identified on radiographs, allowing a specific diagnosis. Although more common in children, when they occur in adults, they are more commonly associated with other injuries. The treatment of cruciate ligament avulsion fractures is different than the treatment of intrasubstance tears of the cruciate ligaments. These injuries can be treated conservatively or surgically with good outcomes. Recently arthroscopic fixation of these injuries with various fixation devices has become more frequent. Treatment largely depends on the type of fracture, particularly, the size, displacement, comminution, and orientation of the avulsed fracture fragment, in addition to the integrity of the attached cruciate ligament. This review article covers the anatomy and biomechanics of the cruciate ligaments, their injury patterns, and approach to management.

Orthopedic Resident and Patient Perception of Electronic Medical Record Use During the Clinic Visit.

Background The transition from paper charts to electronic medical records (EMRs) has resulted in greater efficiency and reduced medical errors. This study aimed to examine the perception of patients and orthopedic residents regarding computer use during the clinic visit. Methodology This study utilized a cross-sectional cluster design. Orthopedic resident physicians were given a one-time general pre-visit survey. Additional surveys were given to patients and resident physicians post-visit. Surveys included questions that assessed satisfaction and the perceived impact of computer usage on doctor-patient interactions. Logistic generalized estimating equations were run to determine if there was an association between patient response and clinician assessment, adjusting for repeated measures within clinicians. Results A total of 80 patients and 15 residents completed the surveys. Results from the physician pre-visit survey showed that more residents perceived the computer as having a "negative" (47%) than "positive" (26%) effect on their relationship with patients. According to the post-visit analysis, patients perceived the residents' use of the EMR as having an overall positive effect on their ability to establish a personal connection and having a positive effect on their ability to give them attention. Conclusions Overall, there was little correlation between patient and resident perception of the computer's effect on their relationship. Patients generally perceived the computer as having a positive effect on their interaction with the residents even when residents had a negative perception of the computer's effect on their interaction.

Enhancement of Chondrogenic Markers by Exosomes Derived from Cultured Human Synovial Fluid-Derived Cells: A Comparative Analysis of 2D and 3D Conditions.

OBJECTIVE: The goal of this pilot study was to investigate the effects of exosomes derived from synovial fluid-derived cells (SFDCs) cultured under normoxic conditions in a two-dimensional (2D) monolayer or encapsulated within a three-dimensional (3D) matrix for chondrogenic differentiation in vitro and cartilage defect repair in vivo. DESIGN: Synovial fluid samples were obtained from three patients, and SFDCs were isolated and expanded either in a 2D monolayer culture or seeded within a transglutaminase cross-linked gelatin (Col-Tgel) to create a 3D gel culture. Exosomes derived from each environment were isolated and characterized. Then, their effects on cartilage-cell proliferation and chondrogenic differentiation were assessed using an in vitro organoid model, and their potential for enhancing cartilage repair was evaluated using a rat cartilage defect model. RESULTS: SFDCs obtained from different donors reached a state of senescence after four passages in 2D culture. However, transferring these cells to a 3D culture environment mitigated the senescence and improved cell viability. The 3D-cultured exosomes exhibited enhanced potency in promoting chondrogenic differentiation, as evidenced by the increased expression of chondrogenic genes and greater deposition of cartilage-specific extracellular matrix. Furthermore, the 3D-cultured exosomes demonstrated superior effectiveness in enhancing cartilage repair and exhibited better healing properties compared to exosomes derived from a 2D culture. CONCLUSIONS: The optimized 3D culture provided a more favorable environment for the proliferation of human synovial cells and the secretion of exosomes compared to the 2D culture. The 3D-cultured exosomes exhibited greater potential for promoting chondrogenic gene expression in vitro and demonstrated improved healing properties in repairing cartilage defects compared to exosomes derived from the 2D culture.

Preoperative Determination of the Size of the Semitendinosus and Gracilis Tendon by Multidetector Row CT Scanner for Anterior Cruciate Ligament Reconstruction.

Accurately measuring the length and diameter of the hamstring tendon autograft preoperatively is important for planning anterior cruciate ligament (ACL) reconstructive surgery. The purpose of this study was to assess the reliability of three-dimensional computed tomography (3D CT) scanning technique to produce the actual measurement of the gracilis and semitendinosus (GT and ST, respectively) tendon grafts' length and diameter for surgery. Ninety patients were scheduled for ACL reconstruction with hamstring autograft. Before the surgery, patients were examined under the multidetector row CT scanner and the ST and GT tendons were qualitatively measured by a volume-rendering technique. The length of ST and GT was measured with 3D CT compared with the length of the harvested ST and GT. The cross-sectional area (CSA) of ST and GT measured with 3D CT compared with the ST and GT graft diameter. Tendon size measured preoperatively and during surgery were statistically compared and correlated. The GT tendons length and cross-sectional area measured during surgery was both shorter and smaller compared with the ST tendon. GT and ST tendon length were correlated to patients' body index such as the height and weight (p < 0.05). However, the correlation levels were low to medium (r = 0.23-0.49). There was strong correlation between the lengths of GT (r = 0.76; p < 0.001) and ST (r = 0.87; p < 0.001) measured with the 3D CT and tendon length at surgery. There was a moderate correlation between graft diameter measured at surgery and 3D CT cross-sectional area (r = 0.31; p < 0.05). A multidetector row CT scanner can determine the ST and GT tendons' length and diameter. These measurements can be used for preoperative planning to help determine the surgical method and counsel patients on appropriate graft choices prior to surgery.

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.

The effects of shoulder laxity on upper extremity blood flow in professional baseball pitchers.

BACKGROUND: The repetitive overhand throwing can potentially cause physiologic or pathologic changes in musculoskeletal and vascular structures. The purpose of this study was to investigate the effects of throwing on upper extremity arterial blood flow before and after a controlled pitching session. The hypothesis is that pitchers with physical signs of shoulder laxity would demonstrate differential changes in upper extremity blood flow as compared to those without laxity. METHODS: Eighteen professional male pitchers underwent a detailed shoulder physical evaluation, followed by a wrist/brachial index (WBI) vascular exam and a vascular ultrasound examination before and after a controlled throwing session. RESULTS: Following a 50-pitch workout, the WBI was significantly lower (0.79-0.86) in pitchers with laxity on exam versus no laxity (P < .05). For all pitchers, the average arterial volume flow increased from 234 ml/min to 482 ml/min after 50 pitches. Pitchers without physical signs of laxity had an average arterial volume flow increase of 115%, while the pitchers with laxity signs increased 35%. CONCLUSION: This study demonstrated a statistically significant decrease in arterial blood flow in the laxity group compared to the nonlaxity throwers.