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

Principles of cartilage tissue engineering in TMJ reconstruction

Diseases and defects of the temporomandibular joint (TMJ), compromising the cartilaginous layer of the condyle, impose a significant treatment challenge. Different regeneration approaches, especially surgical interventions at the TMJ's cartilage surface, are established treatment methods in maxillofacial surgery but fail to induce a regeneration ad integrum. Cartilage tissue engineering, in contrast, is a newly introduced treatment option in cartilage reconstruction strategies aimed to heal cartilaginous defects. Because cartilage has a limited capacity for intrinsic repair, and even minor lesions or injuries may lead to progressive damage, biological oriented approaches have gained special interest in cartilage therapy. Cell based cartilage regeneration is suggested to improve cartilage repair or reconstruction therapies. Autologous cell implantation, for example, is the first step as a clinically used cell based regeneration option. More advanced or complex therapeutical options (extracorporeal cartilage engineering, genetic engineering, both under evaluation in pre-clinical investigations) have not reached the level of clinical trials but may be approached in the near future. In order to understand cartilage tissue engineering as a new treatment option, an overview of the biological, engineering, and clinical challenges as well as the inherent constraints of the different treatment modalities are given in this paper

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

Brachial Plexus Birth Palsy: Rationale for a Multicenter Prospective Study

While the majority of patients with brachial plexus birth palsy (BPBP) demonstrate spontaneous recovery, some will have persistent neurological deficits and functional limitations. Microsurgical repair and/or reconstruction of the brachial plexus are often recommended for these patients; however, the optimal timing of microsurgery is unknown. Furthermore, the long-term outcomes of microsurgery, as compared with natural history and secondary reconstructive surgery, are unknown. The purpose of this article is to present the rationale for the multicenter prospective study of the treatment of BPBP. The current study protocol is provided

Brachial Plexus Birth Palsy: The Boston Children's Hospital Experience

The purpose of this article is to review our institution's experience with and current approach to the treatment of brachial plexus birth palsy (BPBP). Specific focus is made on the microsurgical treatment of extraforaminal nerve ruptures, the effects of long-standing BPBP on glenohumeral development, and the results of secondary reconstructive surgery for shoulder dysfunction in chronic BPBP

Obstetric Brachial Plexus Injuries Following Breech Delivery: An Adverse Experience in The Netherlands

Obstetric brachial palsy following breech delivery is a typical group: upper lesions predominating with a great number of upper root avulsions and phrenic nerve lesions. In some cases spontaneous nerve recovery is insufficient and further treatment is considered in the first months of the infant's life. The results of surgical treatment of 61 cases of upper brachial plexus lesions after vaginal breech delivery who did not recover sufficiently are reported. In this group the following nerve transfers were applied: 51 accessory, 28 medial pectoral, 2 hypoglossal nerve transfers, and in 2 cases transfer of intercostals; in some cases the transfers were part of an extended brachial plexus reconstruction. Generally, the results of both primary and possibly secondary operations in this series were rewarding: 53% good and 20% fair. In both these groups most patients are able to position and use their more or less normal hand such that they can function normally, without serious impairment according to the international classification

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

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