Biodegradable scaffolds seeded with bone marrow mononuclear cells (BMCs) are the earliest tissue-engineered vascular grafts (TEVGs) to be used clinically. These TEVGs transform into living blood vessels in vivo, with an endothelial cell (EC) lining invested by smooth muscle cells (SMCs); however, the process by which this occurs is unclear. To test if the seeded BMCs differentiate into the mature vascular cells of the neovessel, we implanted an immunodeficient mouse recipient with human BMC (hBMC)-seeded scaffolds. As in humans, TEVGs implanted in a mouse host as venous interposition grafts gradually transformed into living blood vessels over a 6-month time course. Seeded hBMCs, however, were no longer detectable within a few days of implantation. Instead, scaffolds were initially repopulated by mouse monocytes and subsequently repopulated by mouse SMCs and ECs. Seeded BMCs secreted significant amounts of monocyte chemoattractant protein-1 and increased early monocyte recruitment. These findings suggest TEVGs transform into functional neovessels via an inflammatory process of vascular remodeling.bone marrow | monocyte chemoattractant protein-1 | tissue engineering | neovascularization C ongenital heart disease is a leading cause of infant mortality, often requiring early surgical intervention to correct fatal cardiovascular malformations. Prosthetic vascular grafts are widely used in these reconstructive operations, but revisions are often necessary because of their inability to grow or effectively remodel within a growing child (1-3). A strategy to address this issue is the use of living tissue-engineered vascular grafts (TEVGs). Constructed from biodegradable polyester tubes seeded with autologous bone marrow mononuclear cells (BMCs), these grafts undergo extensive remodeling in animal recipients and appear to transform into living blood vessels, similar in morphology and function to the native veins into which they are interposed (4, 5). Ongoing clinical studies evaluating BMC-seeded grafts as venous conduits for congenital heart surgery report excellent safety profiles and 100% patency rates at 1-3 years of follow-up (6-8). Additionally, these grafts demonstrate growth potential, suggesting they may be more effective for the pediatric patient population than currently available vascular grafts (8,9).Although the functional efficacy and clinical utility of TEVGs are promising, little is known about how these BMC-seeded polyester tubes transform into living blood vessels in host recipients. It has been proposed that stem cells within the seeded BMC population differentiate into the endothelial cells (ECs) and smooth muscle cells (SMCs) of the developing neovessel, ultimately replacing the degrading polyester tube (10). This hypothesis, however, has not been directly examined.We recently developed a method for constructing small-diameter biodegradable synthetic scaffolds suitable for use as vascular grafts in mice (11). These tubular scaffolds are composed of the same materials and design used in clinical TEVGs...

Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2000 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To identify mutations contributing to common non-syndromic midline (sagittal and metopic) craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 additional probands. Thirteen probands (7%) had damaging de novo or rare transmitted mutations in SMAD6, an inhibitor of BMP -induced osteoblast differentiation (p<10 À20 ). SMAD6 mutations nonetheless showed striking incomplete penetrance (<60%). Genotypes of a common variant near BMP2 that is strongly associated with midline craniosynostosis explained nearly all the phenotypic variation in these kindreds, with highly significant evidence of genetic interaction between these loci via both association and analysis of linkage. This epistatic interaction of rare and common variants defines the most frequent cause of midline craniosynostosis and has implications for the genetic basis of other diseases.

We developed a tissue-engineered vascular graft composed of biodegradable scaffold seeded with autologous bone marrow-derived mononuclear cells (BMMCs) that is currently in clinical trial and developed analogous mouse models to study mechanisms of neovessel formation. We previously reported that seeded human BMMCs were rapidly lost after implantation into immunodeficient mice as host macrophages invaded the graft. As a consequence, the resulting neovessel was entirely of host cell origin. Here, we investigate the source of neotissue cells in syngeneic BMMC-seeded grafts, implanted into immunocompetent mouse recipients. We again find that seeded BMMCs are lost, declining to 0.02% at 14 d, concomitant with host macrophage invasion. In addition, we demonstrate using sex-mismatched chimeric hosts that bone marrow is not a significant source of endothelial or smooth muscle cells that comprise the neovessel. Furthermore, using composite grafts formed from seeded scaffold anastomosed to sex-mismatched natural vessel segments, we demonstrate that the adjacent vessel wall is the principal source of these endothelial and smooth muscle cells, forming 93% of proximal neotissue. These findings have important implications regarding fundamental mechanisms underlying neotissue formation; in this setting, the tissue-engineered construct functions by mobilizing the body's innate healing capabilities to "regenerate" neotissue from preexisting committed tissue cells.

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Purpose-Use of tissue-engineered vascular grafts (TEVGs) in the repair of congenital heart defects provides growth and remodeling potential. Little is known about the mechanisms involved in neovessel formation. We sought to define the role of seeded monocytes derived from bone marrow mononuclear cells (BM-MNCs) on neovessel formation.Methods-Small diameter biodegradable tubular scaffolds were constructed. Scaffolds were seeded with the entire population of BM-MNC (n = 15), BM-MNC excluding monocytes (n = 15), or only monocytes (n = 15) and implanted as infrarenal inferior vena cava (IVC) interposition grafts into severe combined immunodeficiency/bg mice. Grafts were evaluated at 1 week, 10 weeks, or 6 months via ultrasonography and microcomputed tomography, as well as by histologic and immunohistochemical techniques.Results-All grafts remained patent without stenosis or aneurysm formation. Neovessels contained a luminal endothelial lining surrounded by concentric smooth muscle cell layer and collagen similar to that seen in the native mouse IVC. Graft diameters differed significantly between those scaffolds seeded with only monocytes (1.022 ± 0.155 mm) and those seeded without monocytes (0.771 ± 0.121 mm; P = .021) at 6 months. Complications arising from currently available vascular replacement grafts remain a significant source of morbidity and mortality when used in the repair of congenital heart defects. Of particular interest in the pediatric population is the lack of growth and remodeling of replacement conduits after implantation, thereby, necessitating further invasive revisions or reoperations as somatic growth continues. The development of tissue-engineered vascular grafts (TEVGs) provides the potential to overcome such limitations. Modeling our TEVGs on previous work [1-3], we designed a TEVG specifically for use as a conduit in congenital heart surgery where the development of a living, autologous vascular conduit with the ability to repair, remodel, and grow could be best used. Our TEVGs are made by statically seeding autologous human bone marrow-derived mononuclear cells (hBM-MNCs) onto a Conclusions-Monocytes

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Lipoabdominoplasty is not associated with a statistically significant increase in perfusion-related complication rates as compared with traditional abdominoplasty, despite the fact that it involves potential trauma to the vascularity of the elevated abdominoplasty flap. This holds true even in patients who are at increased risk for perfusion-related complications secondary to a history of active smoking or a previous supraumbilical scar.

Background:Le Fort I osteotomy imparts significant changes to the nasolabial region. Past studies have relied on 2-dimensional data and have not delineated differences among various Le Fort I subtypes. The purpose of this study is to 3-dimensionally analyze Le Fort I–induced nasal and lip changes comparing advancement alone versus widening alone [surgically assisted maxillary expansion (SAME)] versus advancement and widening. We hypothesize that the combination of maxillary advancement with widening will result in the most profound changes.Methods:A retrospective cohort study was performed. Included Le Fort I patients were grouped as: (1) nonsegmental straight advancement, (2) widening without advancement, and (3) segmental advancement and widening. Pre- and postoperative 3-dimensional photogrammetry (Canfield) were analyzed. Anthropometric landmarks were placed and measured by 2 independent observers. Statistics involved both paired and unpaired t tests (significance = P < 0.05).Results:One hundred eight photogrammetric data sets were analyzed, including 46 single-piece, 26 SAME, and 36 segmental. Significant postoperative nasal changes were observed within each intragroup analysis. The most dramatic changes were seen after segmental Le Fort I with advancement and widening, which included alar base width, alar width, nostril width, and soft triangle angle, all P < 0.05.Conclusions:Le Fort I osteotomy results in significant alteration of the nasolabial morphology. This is the first study to 3-dimensionally analyze nasal changes that occur comparing maxillary advancement alone versus widening alone (SAME) versus advancement with widening. These objective data permit improved patient counseling and surgical planning.