Antisense mediated blockade of Dickkopf 1 attenuates tumor survival, metastases and bone damage in experimental osteosarcoma.

Osteosarcoma (OS) is the most common primary bone malignancy. The canonical Wnt inhibitor Dickkopf-1 (Dkk-1) has been implicated in bone destruction, tumor survival and metastases during OS. We examined the role of Dkk-1 in OS disease progression and explored strategies for targeting its activity.

Removing the barriers to prehospital blood: A roadmap to success.

This review describes the necessity, evolution, and current state of prehospital blood programs in the United States. Less than 1% of 9-1-1 ground emergency medical service agencies have been able to successfully implement prehospital blood transfusions as part of a resuscitation strategy for patients in hemorrhagic shock despite estimates that annually between 54,000 and 900,000 patients may benefit from its use. The use of prehospital blood transfusions as a tool for managing hemorrhagic shock has barriers to overcome to ensure it becomes widely available to patients throughout the United States.

Scalable manufacture of therapeutic mesenchymal stromal cell products on customizable microcarriers in vertical wheel bioreactors that improve direct visualization, product harvest, and cost.

Background Aims: Human mesenchymal stromal cells (hMSCs) and their secreted products show great promise for treatment of musculoskeletal injury and inflammatory or immune diseases. However, the path to clinical utilization is hampered by donor-tissue variation and the inability to manufacture clinically relevant yields of cells or their products in a cost-effective manner. Previously we described a method to produce chemically and mechanically customizable gelatin methacryloyl (GelMA) microcarriers for culture of hMSCs.

and are coordinately regulated and function as potency biomarkers in human MSCs.

Mesenchymal stem/stromal cells (MSCs) have been evaluated in >1500 clinical trials, but outcomes remain suboptimal because of knowledge gaps in quality attributes that confer potency. We show that TWIST1 directly represses expression that and are inversely correlated across bone marrow-derived MSC (BM-MSC) donor cohorts and predict interdonor differences in their proangiogenic, anti-inflammatory, and immune suppressive activity in vitro and in sterile inflammation and autoimmune type 1 diabetes preclinical models. Transcript profiling of versus BM-MSCs revealed previously unidentified roles for TWIST1/TSG6 in regulating cellular oxidative stress and TGF-β2 in modulating expression and anti-inflammatory activity.

Morpholino-driven blockade of Dkk-1 in osteosarcoma inhibits bone damage and tumour expansion by multiple mechanisms.

Background: Osteosarcoma (OS) is the most common primary bone malignancy. Chemotherapy plays an essential role in OS treatment, potentially doubling 5-year event-free survival if tumour necrosis can be stimulated. The canonical Wnt inhibitor Dickkopf-1 (Dkk-1) enhances OS survival in part through upregulation of aldehyde-dehydrogenase-1A1 which neutralises reactive oxygen species originating from nutritional stress and chemotherapeutic challenge.

A scalable system for generation of mesenchymal stem cells derived from induced pluripotent cells employing bioreactors and degradable microcarriers.

Human mesenchymal stem cells (hMSCs) are effective in treating disorders resulting from an inflammatory or heightened immune response. The hMSCs derived from induced pluripotent stem cells (ihMSCs) share the characteristics of tissue derived hMSCs but lack challenges associated with limited tissue sources and donor variation. To meet the expected future demand for ihMSCs, there is a need to develop scalable methods for their production at clinical yields while retaining immunomodulatory efficacy.

Automated mesenchymal stem cell segmentation and machine learning-based phenotype classification using morphometric and textural analysis.

: Mesenchymal stem cells (MSCs) have demonstrated clinically relevant therapeutic effects for treatment of trauma and chronic diseases. The proliferative potential, immunomodulatory characteristics, and multipotentiality of MSCs in monolayer culture is reflected by their morphological phenotype. Standard techniques to evaluate culture viability are subjective, destructive, or time-consuming.

Characterization of a pluripotent stem cell-derived matrix with powerful osteoregenerative capabilities.

Approximately 10% of fractures will not heal without intervention. Current treatments can be marginally effective, costly, and some have adverse effects. A safe and manufacturable mimic of anabolic bone is the primary goal of bone engineering, but achieving this is challenging.

Patient-Reported Outcomes After Structural Autograft for Large or Cystic Talar Dome Osteochondral Lesions.

Background: While smaller talar dome osteochondral lesions (OCLs) are successfully treated with bone marrow stimulation techniques, the optimal treatment for large or cystic OCLs remains controversial. This study tested the hypothesis that transferring structural autograft bone from the distal tibia to the talus for large or cystic OCLs improves pain and function.

Methods: Thirty-two patients with large or cystic OCLs underwent structural bone grafting from the ipsilateral distal tibia to the talar dome.

Natural History of Avascular Necrosis in the Talus: When to Operate.

Avascular necrosis (AVN) of the talus bone is a progressive and debilitating consequence of trauma or exposure to a variety of risk factors. The Ficat classification describes current understanding of the natural history of AVN, including preclinical, preradiographic, precollapse, postcollapse, and arthritic stages. The size and location of the avascular region likely determines risk of progression; however, symptoms do not correlate with stage.

Scandinavian Total Ankle Replacement: 15-Year Follow-up.

Background: Over the past decade, total ankle arthroplasty (TAA) has become a mainstay in the treatment of end-stage ankle arthritis. Currently in its fourth generation, the Scandanavian Total Ankle Replacement (STAR) is the only 3-piece mobile bearing ankle prosthesis available in the United States. Our current study reports implant survivorship at 15 years and patient outcomes for a subset of these survivors available for study.

Implementation of Patient-Reported Outcomes Measurement Information System Data Collection in a Private Orthopedic Surgery Practice.

Background: The authors describe a method of collecting patient-reported outcomes (PROs) using computerized adaptive tests (CATs) in a high-volume orthopedic surgery practice with limited resources and no research coordinator.

Methods: Patient-Reported Outcomes Measurement Information System CATs were collected prospectively for all clinic patients using a tablet and recorded in the electronic medical record. Scores were compared with validated national norms using single-variable t tests.

Association of Short-term Complications With Procedures Through Separate Incisions During Total Ankle Replacement.

Background: Surgeons disagree about the safety of adding adjuvant procedures requiring separate incisions during total ankle replacement (TAR). This study tested the hypothesis that complication rates for patients in the first year after TAR would be greater when combined with procedures through separate incisions.

Methods: A retrospective review was performed on a consecutive series of 124 patients who underwent total ankle replacement between 2007 and 2013.

Safe zone for placement of talar screws when fusing the ankle with an anterior plating system.

Background: Ankle fusions fixed with anterior plates use fluoroscopic guidance to direct screws toward the subtalar joint. Special imaging views that visualize the subtalar joint are difficult to use and can be unreliable. This study evaluated whether a single lateral ankle view would provide adequate information to judge whether a screw penetrated the subtalar joint and identified strategies that would improve this technique.

The "not so simple" ankle fracture: avoiding problems and pitfalls to improve patient outcomes.

Ankle fractures are among the most common injuries managed by orthopaedic surgeons. Many ankle fractures are simple, with straightforward management leading to successful outcomes. Some fractures, however, are challenging, and debate arises regarding the best treatment to achieve an optimal outcome.

Osteoarthritis of the ankle: the role of arthroplasty.

Total ankle arthroplasty was developed to reduce pain and retain motion of the ankle joint in patients with osteoarthritis. The ankle joint has unique, complex anatomic and biomechanical characteristics that must be considered in a successful total ankle arthroplasty prosthesis. Initial designs from the 1960s to the 1970s had many failures.

Fixation of osteoporotic distal fibula fractures: A biomechanical comparison of locking versus conventional plates.

The increased use of locking plates to treat difficult fracture scenarios has been advocated in patients that have reduced bone mineral density. One of these difficult fracture patterns, fixation of the distal fragment of a distal fibula fracture, may depend on unicortical and cancellous bony purchase. This study investigated the construct stiffness afforded by using locking and conventional plating schema in a cadaveric model.

Subtalar joint arthrodesis using a single lag screw.

Background: This study tested the hypotheses that fusing the subtalar joint with a single lag screw from the posteroinferior calcaneus to the anterior talar neck is an effective technique and that factors affecting the time to fusion can be identified.

Methods: Between October, 1995, and July, 2002, the senior author (RAM) performed 101 isolated subtalar arthrodeses using a technique of single lag-screw fixation from posteroinferior to anterosuperior across the posterior facet of the subtalar joint combined with the application of an autograft taken from the floor of the sinus tarsi and anterior process. The average patient age was 52 (range 17 to 82) years.

Ankle arthroplasty with preoperative coronal plane deformity: short-term results.

The treatment of coronal plane deformity during total ankle arthroplasty is understood poorly. This study tests the hypotheses that preoperative coronal plane malalignment and incongruence of the ankle can be corrected and maintained for 2 years with total ankle replacement, and that factors can be identified that place ankles at risk of having progressive edge-loading develop. Of 86 consecutive patients who had total ankle replacement, 35 had preoperative coronal plane alignment > or =10 degrees.

Perioperative complication rate of total ankle replacement is reduced by surgeon experience.

Background: Recent studies suggest the perioperative complication rate of total ankle arthroplasty decreases as a surgeon becomes familiar with the procedure. This study tests the hypothesis that the number of perioperative adverse events will decrease as surgeon experience with total ankle replacement increases.

Methods: Ten surgeons completed retrospective chart and radiographic reviews of their first 10 cases as well as 10 subsequent cases of the Scandinavian Total Ankle Replacement (STAR).

Metachronous multicentric giant cell tumor: a case report and literature review.

Metachronous multicentric giant cell tumors of bone are rare. The case of a 47-year-old woman who had a giant cell tumor of the ilium develop 24 years after resection of a giant cell tumor of the proximal tibia is reported. The initial and current surgical approaches for this patient are described.

Biomechanical testing of bioabsorbable cannulated screws for slipped capital femoral epiphysis fixation.

This study compared cannulated 4.5-mm bioabsorbable screws made of self-reinforced poly-levolactic acid to cannulated 4.5-mm steel and titanium screws for resistance to shear stress and ability to generate compression in a polyurethane foam model of slipped capital femoral epiphysis fixation.

The University of California at San Francisco international orthopaedic elective.

International volunteerism helps remedy global inequities in orthopaedic care and provides relief for increasing professional disillusionment experienced by many orthopaedic surgeons in the United States. From 1992 to 1998, 41% of residents from the Department of Orthopaedic Surgery at the University of California, San Francisco volunteered overseas. Approximately one half of those have continued volunteering internationally after residency, including many who led later trips with residents.