The state of the art of osseointegration for limb prosthesis.

Osseointegration (OI) is the direct attachment of bone onto a titanium implant. Recently, the term is used to describe "transdermal" implants that allow an external prosthesis to be connected directly to the skeleton. This technology eliminates the challenges of conventional socket-based prostheses, such as skin breakdown and poor fit, which are common in patients with major extremity amputations. Osseointegration patients demonstrate encouraging improvements in quality of life and function. Patients report improvement in prosthetic use, prosthetic mobility, global health, and pain reduction on a variety of clinical assessment tools. Various implants have been developed for osseointegration for amputees. These implants use a variety of fixation strategies and surface augments to allow for successful integration into the host bone. Regardless of design, all OI implants face similar challenges, particularly infections. Other challenges include the inability to determine when integration has occurred and the inability to detect loss of integration. These challenges may be met by incorporating sensing systems into the implants. The percutaneous nature of the metal devices can be leveraged so that internal sensors need not be wireless, and can be interrogated by external monitoring systems, thus providing crucial, real-time information about the state of the implant. The purpose of this review is to (1) review the basic science behind osseointegration, (2) provide an overview of current implants, practice patterns, and clinical outcomes, and (3) preview sensor technologies which may prove useful in future generations of transdermal orthopaedic implants.

Mirna biogenesis pathway is differentially regulated during adipose derived stromal/stem cell differentiation.

Stromal/stem cell differentiation is controlled by a vast array of regulatory mechanisms. Included within these are methods of mRNA gene regulation that occur at the level of epigenetic, transcriptional, and/or posttranscriptional modifications. Current studies that evaluate the posttranscriptional regulation of mRNA demonstrate microRNAs (miRNAs) as key mediators of stem cell differentiation through the inhibition of mRNA translation. miRNA expression is enhanced during both adipogenic and osteogenic differentiation; however, the mechanism by which miRNA expression is altered during stem cell differentiation is less understood. Here we demonstrate for the first time that adipose-derived stromal/stem cells (ASCs) induced to an adipogenic or osteogenic lineage have differences in strand preference (-3p and -5p) for miRNAs originating from the same primary transcript. Furthermore, evaluation of miRNA expression in ASCs demonstrates alterations in both miRNA strand preference and 5'seed site heterogeneity. Additionally, we show that during stem cell differentiation there are alterations in expression of genes associated with the miRNA biogenesis pathway. Quantitative RT-PCR demonstrated changes in the Argonautes (AGO1-4), Drosha, and Dicer at intervals of ASC adipogenic and osteogenic differentiation compared to untreated ASCs. Specifically, we demonstrated altered expression of the AGOs occurring during both adipogenesis and osteogenesis, with osteogenesis increasing AGO1-4 expression and adipogenesis decreasing AGO1 gene and protein expression. These data demonstrate changes to components of the miRNA biogenesis pathway during stromal/stem cell differentiation. Identifying regulatory mechanisms for miRNA processing during ASC differentiation may lead to novel mechanisms for the manipulation of lineage differentiation of the ASC through the global regulation of miRNA as opposed to singular regulatory mechanisms.

The Compress® transcutaneous implant for rehabilitation following limb amputation.

Amputation is an unfortunate outcome of a variety of orthopedic conditions. Many amputees can be functionally fitted with conventional suspension sockets. A substantial subset, however, fails this conventional treatment and is unable to function. In Europe, an alternative to socket-based prostheses has been available for 25 years. Patients there who are unable to functionally use socket-based prostheses have been offered the possibility for transcutaneous osseointegration. With this technology, the prosthetic limb can be rigidly attached to the residual bone, and the socket is eliminated, in many cases enabling improved function and patient satisfaction. In the United States, regulatory barriers have greatly limited the adoption and acceptance of transdermal osseointegration. The Compress® device was developed as an alternate means of fixation for massive endoprostheses, such as distal femoral replacements. A uniquely designed prosthesis is rigidly anchored to the end of the cortical bone and is then subjected to a large axial stress. The bone then grows avidly into the device, providing permanent osseointegration. We have recently adopted this device for transcutaneous use. These procedures have been performed in the United States on a custom regulatory basis. Results of this have been encouraging, and we are planning to begin a regulatory trial in the near future.

The development of a rat model to investigate the formation of blast-related post-traumatic heterotopic ossification.

Currently, there is no animal model in which to evaluate the underlying physiological processes leading to the heterotopic ossification (HO) which forms in most combat-related and blast wounds. We sought to reproduce the ossification that forms under these circumstances in a rat by emulating patterns of injury seen in patients with severe injuries resulting from blasts. We investigated whether exposure to blast overpressure increased the prevalence of HO after transfemoral amputation performed within the zone of injury. We exposed rats to a blast overpressure alone (BOP-CTL), crush injury and femoral fracture followed by amputation through the zone of injury (AMP-CTL) or a combination of these (BOP-AMP). The presence of HO was evaluated using radiographs, micro-CT and histology. HO developed in none of nine BOP-CTL, six of nine AMP-CTL, and in all 20 BOP-AMP rats. Exposure to blast overpressure increased the prevalence of HO. This model may thus be used to elucidate cellular and molecular pathways of HO, the effect of varying intensities of blast overpressure, and to evaluate new means of prophylaxis and treatment of heterotopic ossification.

Blast injuries and heterotopic ossification.

Heterotopic ossification (HO) is perhaps the single most significant obstacle to independence, functional mobility, and return to duty for combat-injured veterans of Operation Enduring Freedom and Operation Iraqi Freedom. Recent research into the cause(s) of HO has been driven by a markedly higher prevalence seen in these wounded warriors than encountered in previous wars or following civilian trauma. To that end, research in both civilian and military laboratories continues to shed light onto the complex mechanisms behind HO formation, including systemic and wound specific factors, cell lineage, and neurogenic inflammation. Of particular interest, non-invasive in vivo testing using Raman spectroscopy may become a feasible modality for early detection, and a wound-specific model designed to detect the early gene transcript signatures associated with HO is being tested. Through a combined effort, the goals of early detection, risk stratification, and development of novel systemic and local prophylaxis may soon be attainable.