Mesenchymal Progenitor Cells and Their Orthopedic Applications: Forging a Path towards Clinical Trials

Mesenchymal progenitor cells (MPCs) are nonhematopoietic multipotent cells capable of differentiating into mesenchymal and nonmesenchymal lineages. While they can be isolated from various tissues, MPCs isolated from the bone marrow are best characterized. These cells represent a subset of bone marrow stromal cells (BMSCs) which, in addition to their differentiation potential, are critical in supporting proliferation and differentiation of hematopoietic cells. They are of clinical interest because they can be easily isolated from bone marrow aspirates and expanded in vitro with minimal donor site morbidity. The BMSCs are also capable of altering disease pathophysiology by secreting modulating factors in a paracrine manner. Thus, engineering such cells to maximize therapeutic potential has been the focus of cell/gene therapy to date. Here, we discuss the path towards the development of clinical trials utilizing BMSCs for orthopaedic applications. Specifically, we will review the use of BMSCs in repairing critical-sized defects, fracture nonunions, cartilage and tendon injuries, as well as in metabolic bone diseases and osteonecrosis. A review of www.ClinicalTrials.gov of the United States National Institute of Health was performed, and ongoing clinical trials will be discussed in addition to the sentinel preclinical studies that paved the way for human investigations

Lysophosphatidic Acid Acyltransferase β (LPAATβ) Promotes the Tumor Growth of Human Osteosarcoma

Osteosarcoma is the most common primary malignancy of bone with poorly characterized molecular pathways important in its pathogenesis. Increasing evidence indicates that elevated lipid biosynthesis is a characteristic feature of cancer. We sought to investigate the role of lysophosphatidic acid acyltransferase β (LPAATβ, aka, AGPAT2) in regulating the proliferation and growth of human osteosarcoma cells. LPAATβ can generate phosphatidic acid, which plays a key role in lipid biosynthesis as well as in cell proliferation and survival. Although elevated expression of LPAATβ has been reported in several types of human tumors, the role of LPAATβ in osteosarcoma progression has yet to be elucidated.Endogenous expression of LPAATβ in osteosarcoma cell lines is analyzed by using semi-quantitative PCR and immunohistochemical staining. Adenovirus-mediated overexpression of LPAATβ and silencing LPAATβ expression is employed to determine the effect of LPAATβ on osteosarcoma cell proliferation and migration in vitro and osteosarcoma tumor growth in vivo. We have found that expression of LPAATβ is readily detected in 8 of the 10 analyzed human osteosarcoma lines. Exogenous expression of LPAATβ promotes osteosarcoma cell proliferation and migration, while silencing LPAATβ expression inhibits these cellular characteristics. We further demonstrate that exogenous expression of LPAATβ effectively promotes tumor growth, while knockdown of LPAATβ expression inhibits tumor growth in an orthotopic xenograft model of human osteosarcoma.Our results strongly suggest that LPAATβ expression may be associated with the aggressive phenotypes of human osteosarcoma and that LPAATβ may play an important role in regulating osteosarcoma cell proliferation and tumor growth. Thus, targeting LPAATβ may be exploited as a novel therapeutic strategy for the clinical management of osteosarcoma. This is especially attractive given the availability of selective pharmacological inhibitors

Bone morphogenetic protein-9 effectively induces osteogenic differentiation of reversibly immortalized calvarial mesenchymal progenitor cells

AbstractCritical-sized craniofacial defect repair represents a significant challenge to reconstructive surgeons. Many strategies have been employed in an effort to achieve both a functionally and cosmetically acceptable outcome. Bone morphogenetic proteins (BMPs) provide a robust osteoinductive cue to stimulate bony growth and remodeling. Previous studies have suggested that the BMP-9 isoform is particularly effective in promoting osteogenic differentiation of mesenchymal progenitor cells. The aim of this study is to characterize the osteogenic capacity of BMP-9 on calvarial mesenchymal progenitor cell differentiation. Reversibly immortalized murine calvarial progenitor cells (iCALs) were infected with adenoviral vectors encoding BMP-9 or GFP and assessed for early and late stages of osteogenic differentiation in vitro and for osteogenic differentiation via in vivo stem cell implantation studies. Significant elevations in alkaline phosphatase (ALP) activity, osteocalcin (OCN) mRNA transcription, osteopontin (OPN) protein expression, and matrix mineralization were detected in BMP-treated cells compared to control. Specifically, ALP activity was elevated on days 3, 7, 9, 11, and 13 post-infection and OCN mRNA expression was elevated on days 8, 10, and 14 in treated cells. Additionally, treatment groups demonstrated increased OPN protein expression on day 10 and matrix mineralization on day 14 post-infection relative to control groups. BMP-9 also facilitated the formation of new bone in vivo as detailed by gross, microcomputed tomography, and histological analyses. Therefore, we concluded that BMP-9 significantly stimulates osteogenic differentiation in iCALs, and should be considered an effective agent for calvarial tissue regeneration

A Simple, Safe Technique for Thorough Seroma Evacuation in the Outpatient Setting

Summary: Seroma formation, a common postoperative complication in reconstructive cases, can lead to capsular contracture and increased office visits and expenses. The authors present a safe, novel technique for ensuring the thorough removal of serous fluid in the outpatient setting. By relying on access with an angiocatheter, potential injury to permanent implants is minimized. The use of low continuous wall suction obviates the need of manual suction via multiple syringes and offers a rapid and thorough evacuation of all types of seromas

SSET Project: Cost-effectiveness Analysis of Surgical Specialty Emergency Trays in the Emergency Department

Background:. We hypothesize that reusable, on-site specialty instrument trays available to plastic surgery residents in the emergency department (ED) for bedside procedures are more cost-effective than disposable on-site and remote re-usable operating room (OR) instruments at our institution. Methods:. We completed a cost-effectiveness analysis comparing the use of disposable on-site kits and remote OR trays to a hypothetical, custom, reusable tray for ED procedures completed by PRS residents. Material costs of existing OR trays were used to estimate the purchasing and use-cost of a custom on-site tray for the same procedures. Cost of per procedure ‘consult time’ was estimated using procedure and resident salary. Results:. Sixteen bedside procedures were completed over a 4.5 month period. A mean of 2.14 disposable kits were used per-procedure. Mean consultation time was 1.66 hours. Procedures that used OR trays took 3 times as long as procedures that used on-site kits (4 vs. 1.1 hours). Necessary, additional instruments were unavailable for 75% of procedures. Mean cost of using disposable kits and OR trays was $115.03/procedure versus an estimated$26.67/procedure cost of using a custom tray, yielding $88.36/procedure cost-savings. Purchase of a single custom tray ($1,421.55) would be redeemed after 2.3 weeks at 1 procedure/day. Purchasing 4 trays has projected annual cost-savings of $26,565.20. Conclusion:. The purchase of specialized procedure trays will yield valuable time and cost-savings while providing quality patient care. Improving time efficiency will help achieve the Accreditation Council of Graduate Medical Education (ACGME) goals of maintaining resident well-being and developing quality improvement competency

Immediate Dental Implantation in Oncologic Jaw Reconstruction: Workflow Optimization to Decrease Time to Full Dental Rehabilitation

Summary:. Full dental rehabilitation following segmental mandibulectomy or maxillectomy for oncologic tumor ablation should be the goal for every patient. But despite advances in technology and reconstructive techniques, many patients do not achieve timely or complete oral rehabilitation. Recognizing this fault, we recently adopted an innovative workflow to increase the number of patients undergoing dental restoration, irrespective of tumor pathology or need for adjuvant radiotherapy. Preoperatively, every osseous jaw reconstruction undergoes virtual surgical planning to incorporate the placement of endosseous implants into the fibula osteocutaneous free flap. The dental implants are then placed intraoperatively at the time of tumor ablation and reconstruction. Four-to-six weeks following the initial surgery, the patient returns to the operating room for vestibuloplasty and exposure of the dental implants. Within 3 days of the vestibuloplasty, a temporary dental prosthesis is placed in the dental clinic, and the patient can then begin radiation therapy if needed. Following adjuvant radiation therapy, the temporary prosthesis can be replaced with a permanent one. At our institution, this innovative workflow has allowed for earlier aesthetic restoration of the jaw and greatly expanded the number of patients able to achieve oral rehabilitation. Herein, we describe this innovative workflow and provide technical pearls for successful execution

SARS-CoV-2 vaccination modelling for safe surgery to save lives: data from an international prospective cohort study

Background Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18-49, 50-69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty. Results NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year. Conclusion As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population.The aim of this study was to inform vaccination prioritization by modelling the impact of vaccination on elective inpatient surgery. The study found that patients aged at least 70 years needing elective surgery should be prioritized alongside other high-risk groups during early vaccination programmes. Once vaccines are rolled out to younger populations, prioritizing surgical patients is advantageous