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Geometric ring annuloplasty has shown promise during bicuspid aortic valve repair for aortic insufficiency. This study examined early outcomes of bicuspid aortic valve repair associated with proximal aortic aneurysm replacement.From September 2017 to November, 2021, 127 patients underwent bicuspid aortic valve repair with concomitant proximal aneurysm reconstruction. Patient age was 50.6 ± 12.7 years (mean ± standard deviation), male gender was 83%, New York Heart Association Class was 2 (1-2) (median [interquartile range]), and preoperative aortic insufficiency grade was 3 (2-4). Ascending aortic diameter was 50 (46-54) mm, and all patients had ascending aortic replacement. Forty patients had sinus diameters greater than 45 mm, prompting remodeling root procedures. A total of 105 patients had Sievers type 1 valves, 3 patients had type 0, and 7 patients had type 2. A total of 118 patients had primarily right/left fusion, 8 patients had right/nonfusion, and 1 patient had left/nonfusion. Leaflet reconstruction used central leaflet plication and cleft closure, with limited ultrasonic decalcification in 31 patients.Ring size was 23 (21-23) mm, and 26 of 40 root procedures were selective nonfused sinus replacements. Aortic clamp time was 139 (112-170) minutes, and bypass time was 178 (138-217) minutes. Postrepair aortic insufficiency grade was 0 (0-0) (Geometric ring annuloplasty for bicuspid aortic valve repair with proximal aortic aneurysm reconstruction is safe and associated with good early outcomes. Further experience and follow-up will help inform long-term durability.

Reoperative aortic root replacement, following prior biologic or mechanical valved conduit aortic root prosthesis, presents a technical challenge. The rapid-deployment aortic valve prosthesis is an approved alternative to traditional bioprosthetic aortic valve replacement. We present three clinical cases in which rapid-deployment aortic valve prostheses were utilized in lieu of reoperative full aortic root replacement. All three patients recovered uneventfully. The rapid-deployment valve insertion in a prior surgical aortic root prosthesis is a safe option to avoid reoperative full aortic root replacement.

Medical management remains the mainstay of treatment for patients who present with acute Type-B aortic dissections (TBAD). However, it is unclear whether patients maintain adherence to their anti-impulse therapy medication regimen following hospital discharge. This study was designed to evaluate rates and predictors of medication adherence among insured patients treated for acute TBAD.We used the Truven MarketScan database to identify US patients who presented with an acute TBAD between 2008 to 2017. Patients with continuous health insurance (Commercial or Medicare Part C) for at least 12 months after TBAD diagnosis were stratified by whether they underwent open surgical repair (OPEN), thoracic endovascular aortic repair (TEVAR), or only medication management (MED). Prescriptions for anti-impulse therapy medications were captured and adherence was defined by the medication possession ratio as80% fill rate over the follow-up period. Mixed-effects logistic regression models were used to identify predictors for medication adherence.A total of 6,702 patients were identified that underwent treatment for TBAD (3% TEVAR, 9% OPEN,74% MED), whereas 14% received no intervention. The overall mean (±SD) rate of adherence to anti-impulse therapy was 72.6% ( ± 26), and varied based on type of TBAD intervention (73.4% TEVAR, 74.4% OPEN,72.4% MED). The majority of patients across all treatment groups were prescribed ≥ 2 agents, with beta-blockers and diuretics being the most common medication classes. The odds of adherence to anti-impulse therapy were significantly lower for patients who were female (OR: 0.93; 95%CI:0.85-0.99; P = 0.03), aged45 years (OR: 0.81; 95%CI:0.69-0.96; P0.001), nonadherent on preexisting therapy (OR: 0.81; 95%CI: 0.73-0.89; P0.001), and when medications were obtained in less than a 90 days supply from retail pharmacies.Nearly a quarter of patients were nonadherent with anti-impulse therapy prescribed following an acute TBAD, which was more likely among younger female patients not adherent before their event. Adherence was improved among patients who received their medications by mail and when a90 days supply was prescribed. These findings may be used by quality improvement initiatives to improve medication adherence following TBAD and help prevent further complications.

BACKGROUNDpostoperative atrial fibrillation (POAF) is a common cardiac surgery complication that is associated with increased complications and negative outcomes, but the association between presurgical atrial conduction abnormalities and POAF has not been investigated clinically during premature atrial S1S2 stimulation. This clinical study sought to examine whether intraoperative premature atrial stimulation reveals increased areas of slowed and/or blocked conduction in patients that develop POAF.METHODSHigh-density intraoperative epicardial left atrial mapping was conducted in 20 cardiac surgery patients with no prior history of atrial fibrillation (AF). In 20 patients, 6 (30%) developed POAF. A flexible-array of 240-electrodes was placed on the posterior left atrial wall in between the pulmonary veins. Activation maps were generated for sinus and premature atrial S1S2 stimulated beats. The area of conduction block (CB), conduction delay (CD) and the combination of both (CDCB) for conduction velocity RESULTSFor a premature atrial S2 beat with shortest cycle length captured, conduction velocity maps revealed a significantly higher area for CD (13.19±6.59 versus 6.06±4.22 mm2, p=0.028) and CDCB (17.36±8.75 versus 7.41±6.39 mm2, p=0.034), and a trend toward a larger area for CB (4.17±3.66 versus 1.34±2.86 mm2, p=0.063) in patients who developed POAF in comparison to those that remained in the sinus. Sinus and S1 paced beats did not show substantial differences in abnormal conduction areas between patients with and without POAF.CONCLUSIONIn comparison to sinus and S1 beats, premature atrial S2 beats accentuate conduction abnormalities in cardiac surgery patients that developed POAF.

National and institutional quality initiatives provide benchmarks for evaluating the effectiveness of medical care. However, the dramatic growth in the number and type of medical and organizational quality-improvement standards creates a challenge to identify and understand those that most accurately determine quality in cardiac surgery. It is important that surgeons have knowledge and insight into valid, useful indicators for comparison and improvement. We therefore reviewed the medical literature and have identified improvement initiatives focused on cardiac surgery. We discuss the benefits and drawbacks of existing methodologies, such as comprehensive regional and national databases that aid self-evaluation and feedback, volume-based standards as structural indicators, process measurements arising from evidence-based research, and risk-adjusted outcomes. In addition, we discuss the potential of newer methods, such as patient-reported outcomes and composite measurements that combine data from multiple sources.

Transcatheter aortic valve implantation (TAVI) is now routinely performed in patients with aortic stenosis with low mortality and complication rates. Although periprocedural risks have been substantially minimized, procedure- and contrast-induced acute kidney injury (AKI) remains a major concern. AKI remains a frequent complication of contrast-guided interventional procedures and is associated with a significantly adverse prognosis. We review the currently available clinical data related to AKI, with emphasis on contrast-induced nephropathy (CIN), and discuss a novel, integrated approach aiming to minimize AKI risk in high-risk patients. A stepwise algorithm is also proposed for the management of these complex patients.

Introduction: Postoperative atrial fibrillation (POAF) is a common cardiac surgery complication that is highly associated with increased morbidity and mortality. The relation of presurgical left atrial (LA) conduction abnormalities and POAF during intraoperative premature atrial stimulation (S1S2) pacing is investigated and reported. Hypothesis: Intraoperative premature atrial stimulation reveals increased areas of slowed or blocked conduction in patients that develop POAF. Methods: High-density intraoperative epicardial mapping was conducted in 20 cardiac surgery patients with no history of preoperative atrial fibrillation (AF) both in sinus rhythm (SR) and during S1S2 pacing. A flexible array comprised of 240 electrodes was placed on the posterior LA wall in between the pulmonary veins. For each patient, the area of conduction block (CB), conduction delay (CD) and combined conduction delay and block (CDCB) for conduction velocity Results: In 20 patients, 6 (30%) developed POAF. As shown in the Figure, conduction maps revealed the presence of significantly higher areas of CD (13.2±6.6% vs. 6.1±4.2%, p=0.03) and CDCB (17.5±8.7% vs. 7.4±6.4%, p=0.03), and a trend toward larger CB (4.2±3.8% vs. 1.3±2.9%, p=0.09) in patients that developed POAF for premature atrial beat S2 compared to patients that remained in SR after cardiac surgery. S1 paced beats and SR did not show significant differences in abnormal conduction percentages between patients with and without POAF. Conclusions: Premature atrial stimulation accentuates conduction abnormalities in cardiac surgery patients that develop POAF, revealing a pre-surgical substrate that may indicate greater risk for post-surgical atrial arrhythmias.

Acute changes to left ventricular (LV) hemodynamics after transcatheter aortic valve replacement (TAVR) in humans have been sparsely investigated and informed largely by computer simulation of hypothetical pressure-volume (PV) loops. PV loops are the gold standard for evaluating mechanical

Acute ambient air pollution exposure increases risk of cardiac events. We evaluated sex-and-age-specific effects of PM2.5 on hospital readmission and death among 19,602 Medicare beneficiaries (Nevents = 30,510) who survived cardiovascular events including myocardial infarction (MI), heart failure (HF), ischemic heart disease (IHD), and cardiac arrhythmias in Utah from 1999&ndash, 2009. Fine and Gray regression jointly modeled the effect of PM2.5 on readmission hazard rates while allowing for the competing risk of death. Models were stratified by age and sex and adjusted for Charlson Comorbidity Index, dual enrollment in Medicare Parts A and B, temperature, and household income. There were 2032 cardiac readmissions and 1420 deaths after discharge. Among males age 65&ndash, 74 years admitted for HF, a 10 &mu, m/m3 increase in PM2.5 was associated with a 30% increase in risk of readmission (p = 0.01). Among females age 75&ndash, 84 admitted for HF, PM2.5 was associated with a 22% increase in risk of readmission (p = 0.01). Among females age 75&ndash, 84 years admitted for IHD, PM2.5 was associated with a 25% decrease in readmission (p = 0.01), however this was explained by a 36% increase in risk of death (p = 0.01). Exposure to PM2.5 was associated with increased risk of readmission and death. Associations were dependent upon age, sex, and index condition.

Acute ambient air pollution exposure increases risk of cardiac events. We evaluated sex-and-age-specific effects of PM2.5 on hospital readmission and death among 19,602 Medicare beneficiaries (Nevents = 30,510) who survived cardiovascular events including myocardial infarction (MI), heart failure (HF), ischemic heart disease (IHD), and cardiac arrhythmias in Utah from 1999–2009. Fine and Gray regression jointly modeled the effect of PM2.5 on readmission hazard rates while allowing for the competing risk of death. Models were stratified by age and sex and adjusted for Charlson Comorbidity Index, dual enrollment in Medicare Parts A and B, temperature, and household income. There were 2032 cardiac readmissions and 1420 deaths after discharge. Among males age 65–74 years admitted for HF, a 10 μm/m3 increase in PM2.5 was associated with a 30% increase in risk of readmission (p = 0.01). Among females age 75–84 admitted for HF, PM2.5 was associated with a 22% increase in risk of readmission (p = 0.01). Among females age 75–84 years admitted for IHD, PM2.5 was associated with a 25% decrease in readmission (p = 0.01), however this was explained by a 36% increase in risk of death (p = 0.01). Exposure to PM2.5 was associated with increased risk of readmission and death. Associations were dependent upon age, sex, and index condition.

BACKGROUND Cell therapy with mesenchymal stromal cells is a promising strategy for tissue repair. Restoration of blood flow to ischemic tissues is a key step in wound repair, and mesenchymal stromal cells have been shown to be proangiogenic. Angiogenesis is critically regulated by the hypoxia-inducible factor (HIF) superfamily, consisting of transcription factors targeted for degradation by prolyl hydroxylase domain (PHD)-2. The aim of this study was to enhance the proangiogenic capability of mesenchymal stromal cells and to use these modified cells to promote wound healing. METHODS Mesenchymal stromal cells harvested from mouse bone marrow were transduced with short hairpin RNA (shRNA) against PHD-2; control cells were transduced with scrambled shRNA (shScramble) construct. Gene expression quantification, human umbilical vein endothelial cell tube formation assays, and wound healing assays were used to assess the effect of PHD knockdown mesenchymal stromal cells on wound healing dynamics. RESULTS PHD-2 knockdown mesenchymal stromal cells overexpressed HIF-1α and multiple angiogenic factors compared to control (p < 0.05). Human umbilical vein endothelial cells treated with conditioned medium from PHD-2 knockdown mesenchymal stromal cells exhibited increased formation of capillary-like structures and enhanced migration compared with human umbilical vein endothelial cells treated with conditioned medium from shScramble-transduced mesenchymal stromal cells (p < 0.05). Wounds treated with PHD-2 knockdown mesenchymal stromal cells healed at a significantly accelerated rate compared with wounds treated with shScramble mesenchymal stromal cells (p < 0.05). Histologic studies revealed increased blood vessel density and increased cellularity in the wounds treated with PHD-2 knockdown mesenchymal stromal cells (p < 0.05). CONCLUSIONS Silencing PHD-2 in mesenchymal stromal cells augments their proangiogenic potential in wound healing therapy. This effect appears to be mediated by overexpression of HIF family transcription factors and up-regulation of multiple downstream angiogenic factors.

Author(s): Nguyen, Heajung L; Calfon Press, Marcella A; Aboulhosn, Jamil A; Lin, Jeannette P; Benharash, Peyman; Yang, Eric H

We present a challenging case of early bioprosthetic valve degeneration following valve-in-valve transcatheter aortic valve replacement and bioprosthetic valve fracture.

We describe the patient selection, intraprocedural imaging, and procedural technique for transseptal puncture through the Gore® Cardioform interatrial septal occluder. Due to new indications for PFO closure and increasing need for access to the left atrium via percutaneous approach, we expect an increasing need for utilization of a trans-septal puncture technique through these devices.

Transesophageal echocardiography (TEE) is routinely used for guidance of cardiac procedures, but more and more intraoperative echocardiographers are being asked to apply their knowledge and expertise to areas of noncardiac surgery. We present a case where TEE was used to guide the transcatheter aspiration of tumor/thrombus from the IVC in a patient with renal cell carcinoma who was not an operative candidate. During the procedure a portion of the tumor/thrombus embolizes and TEE was essential for the visualization of this tumor in transit and the subsequent management of the patient. Because the use of TEE for the guidance of these procedures appears to be growing, we used the discussion of this case as an opportunity to put together a step by step guide for the use of TEE in this setting.

Diabetes and its complications are a major public health burden in the developed world. The major cause of diabetic complications is abnormal growth of new blood vessels. This dysfunctional neovascularization results in significant morbidity and mortality in patients with diabetes and, as such, is a major focus of basic and clinical investigation. It has become clear that hyperglycemia disrupts tissue-level signaling in response to hypoxia and ischemia, impairs the vasculogenic potential of circulating stem cells and fundamentally alters the structure and function of key neovascularization proteins, including hypoxia-inducible factor-1. These mechanistic and pathophysiologic studies have revealed new therapeutic targets to restore normal neovascularization and to ameliorate and prevent diabetic vascular complications.

Objectives Systemic allergic reactions to nickel alloys in percutaneous atrial septal defect occlusion devices have a poorly defined natural history. We describe our experience of surgical removal of the offending device in a series of patients with nickel allergy and refractory symptoms. Methods Patients with atrial septal defect device explants for nickel allergy were reviewed. Administered questionnaires focused on symptoms, quality of life, and satisfaction along with the 36-Item Short Form Health Survey to measure physical and mental health postsurgery. Results Atrial septal defect devices were removed for nickel allergy in 58 patients during the past 10 years. The median age was 42 years (range, 24-71 years) and 95% were women. Explantation occurred at a median of 8 years (range, 6 months-18 years) after insertion. Symptoms included fatigue (82%), chest pain (78%), headache (73%), and palpitation (58%). Surveys were available for 45 patients: 58% rated their quality of life as poor and 69% were not at all satisfied with their device. Postexplant, all patients reported improvement in their symptoms, with 18 patients (42%) noting complete resolution. In 12 patients prospectively studied, the preoperative scores in physical and mental health domains were lower than the validation group, indicating significant disability. Similarly, there was marked improvement in each domain postremoval. Conclusions Patients with nickel allergy and severe refractory symptoms after atrial septal defect device implantation experience profound resolution of symptoms and improved quality of life after removal. Nickel allergy should be considered before device insertion, and a low threshold should exist for surgical removal for refractory symptoms.

Objective The objective of this study was to determine if the implementation of a value-driven outcomes tool comprising modifiable quality and utilization metrics lowers cost and improves value of coronary artery bypass grafting (CABG) postoperative care. Methods Ten metrics were defined for CABG patients in 2 temporally separated phases. Clinical care protocols were designed and implemented to increase compliance with these metrics. Clinical outcomes and cost data were harvested from the electronic medical record using a proprietary value-driven outcomes tool and verified by a data management team. "Perfect care" was defined as achieving all 10 metrics per patient episode. Results Over a 45-month period, data of 467 consecutive patients who underwent isolated CABG were analyzed. "Perfect care" was successfully achieved in 304 patients (65.1%). There were no observed differences in mortality between patient groups. Linear regression analysis showed a negative correlation between percent compliance with "perfect care" and mean cost. When multivariate analysis was used to adjust for preoperative risk score, mean cost for patients with "perfect care" was 37.0% less than for those without "perfect care." Conclusions In the context of focused institution-specific interventions to target quality and utilization metrics for CABG care, clinical care pathways and protocols informed by innovative tools that link automated tracking of these metrics to cost data might simultaneously promote quality and decrease costs, thereby enhancing value. This descriptive study provides preliminary support for a systematic approach to define, measure, and modulate the drivers of value for cardiothoracic surgery patients.

Adipose-derived stem cells (ASCs) have shown potential for cell-based therapy in the field of plastic surgery. However, the fate of ASCs after transplantation and the mechanism(s) of their biologic capabilities remain unclear.We isolated and cultured ASCs from transgenic mice that express both luciferase and green fluorescent protein and injected the cells into the inguinal fat pads of wild-type mice. We tested 4 experimental groups, namely, ischemic fat pads with/without ASCs and control fat pads with/without ASCs.Transplanted ASCs were tracked with bioluminescence imaging. The luminescence gradually decreased over 28 days, indicating cell death after transplantation. More ASCs were retained in ischemic fat pads on day 7 compared to control fat pads. On day 14, adipose tissue vascular density was higher in the ASC transplantation groups compared to those without ASCs. On day 28, there was decreased atrophy of adipose tissue in ASC-treated ischemic fat pads. Transplanted ASCs were detected as nonproliferating green fluorescent protein-positive cells, whereas native endothelial cells adjacent to the transplanted ASCs were proliferative. Protein analysis demonstrated higher expression of hepatocyte growth factor and vascular endothelial growth factor in the ASC transplantation groups, suggesting a paracrine mechanism, which was confirmed by in vitro experiments with conditioned media from ASCs.Transplanted ASCs are preferentially retained in ischemic adipose tissue, although most of the cells eventually undergo cell death. They exert an angiogenic effect on adipose tissue mainly through a paracrine mechanism. Increased understanding of these effects will help develop ASCs as a tool for cell-based therapy.

Reduced expression of bone morphogenetic protein receptor 2 subverts a stress granule response, heightens GM-CSF mRNA translation, and increases inflammatory cell recruitment to exacerbate pulmonary arterial hypertension., Idiopathic pulmonary arterial hypertension (PAH [IPAH]) is an insidious and potentially fatal disease linked to a mutation or reduced expression of bone morphogenetic protein receptor 2 (BMPR2). Because intravascular inflammatory cells are recruited in IPAH pathogenesis, we hypothesized that reduced BMPR2 enhances production of the potent chemokine granulocyte macrophage colony-stimulating factor (GM-CSF) in response to an inflammatory perturbation. When human pulmonary artery (PA) endothelial cells deficient in BMPR2 were stimulated with tumor necrosis factor (TNF), a twofold increase in GM-CSF was observed and related to enhanced messenger RNA (mRNA) translation. The mechanism was associated with disruption of stress granule formation. Specifically, loss of BMPR2 induced prolonged phospho-p38 mitogen-activated protein kinase (MAPK) in response to TNF, and this increased GADD34–PP1 phosphatase activity, dephosphorylating eukaryotic translation initiation factor (eIF2α), and derepressing GM-CSF mRNA translation. Lungs from IPAH patients versus unused donor controls revealed heightened PA expression of GM-CSF co-distributing with increased TNF and expanded populations of hematopoietic and endothelial GM-CSF receptor α (GM-CSFRα)–positive cells. Moreover, a 3-wk infusion of GM-CSF in mice increased hypoxia-induced PAH, in association with increased perivascular macrophages and muscularized distal arteries, whereas blockade of GM-CSF repressed these features. Thus, reduced BMPR2 can subvert a stress granule response, heighten GM-CSF mRNA translation, increase inflammatory cell recruitment, and exacerbate PAH.

This chapter focuses on training pathways for cardiothoracic surgery and the pros and cons of traditional pathways, where trainees enter the specialty after completing general surgery residency, and integrated tracks where students match directly into cardiothoracic surgery out of medical school. We will examine why one pathway might be best for you as an individual, but want to emphasize that both pathways lead to successful training and a fruitful career and there is not one ‘best’ way to pursue cardiothoracic surgery.

Ascending aortic aneurysms arising from the native aorta following cardiac transplantation are rare. We report two patients who developed aneurysms of the native ascending aorta requiring surgical repair post-transplantation. Both patients underwent ascending and hemi-arch replacement and recovered uneventfully. Heart transplant patients with pre-existing aortic dilation/ectasia may display more rapid aneurysmal growth compared to non-transplant patients. Therefore close observation is warranted in these patients.

Cardiac arrest is a challenging clinical presentation that emergency medicine providers often encounter. Aortic dissection is an uncommon etiology in all-comers presenting in cardiac arrest. The use of bedside point of care echocardiography to aid in resuscitative efforts is expanding, particularly with the increasing use of transesophageal echocardiography (TEE) by emergency medicine providers. Additionally, emergency department initiation of extracorporeal membrane oxygenation (ECMO) is a relatively newer development in emergency department practice. We report the case of a 64-year old male presenting to the emergency department in cardiac arrest with TEE identification of aortic dissection as the etiology resulting in discontinuation of ECMO initiation attempts.

Although common, the prevalence and impact of treatment on main pulmonary artery (MPA) dilation in Marfan syndrome (MFS) are unclear. We sought to determine the prevalence and progression of MPA dilation (Z score ≥2) and impact of treatment over 3 years using the public dataset from the Pediatric

Background Frostbite injury occurs when exposure to cold results in frozen tissue. To screen drugs and other field therapies that might improve the outcome for a frostbite victim, it would be helpful to have a reliable and cost-effective preclinical in vivo model. Objective We sought to create a novel mouse skin model of induced frostbite injury. This model would allow quantification of the surface area of involved skin, histology of the wound, rate of wound healing, and skin loss in a standardized fashion after the frostbite injury. Methods Thirty-six mice were studied. Standardized 2.9-cm diameter circles were tattooed on the mouse dorsum. Magnets frozen in dry ice (−78.5°C) were used to create a frostbite injury on skin within the circle, either as a continuous 5-minute freeze or as 3 repeated freeze (1-minute) and thaw (3-minute) cycles. Appearance, healing rate, skin surface area loss, and histology were recorded until the wounds were healed. Results The amount of skin surface area loss was approximately 50% for both freeze methods. Although the time to surface skin healing was similar for both freeze methods, the initial healing rate was significantly ( P = .001) slower in mice exposed to the freeze-thaw cycles compared with the continuous freeze model. Histopathology reflected inflammatory changes, cell death, and necrosis. Conclusions This novel in vivo mouse model for frostbite allows quantification of affected skin surface area, histology, healing rate, and skin loss and has the potential of being utilized to screen future treatment modalities.

With the rapidly expanding field of tissue engineering, surgeons have been eager to apply these principles to craniofacial surgery. Tissue engineering strategies combine the use of a cell type placed on a scaffold and subsequently implanted in vivo to address a tissue defect or tissue dysfunction. In this review we will discuss the current clinical need for skeletal and soft tissue engineering faced by craniofacial surgeons and subsequently we will explore cell types and scaffold designs being employed for tissue engineering treatment options. We will conclude by discussing ways to enhance the vascularity of tissue engineered constructs as this will ultimately allow for a definitive repair. Current “stem cell” options include pluripotent stem cells as well as multipotent mesenchymal cells. Biomimetic scaffolds can function to protect and enhance differentiation of stem cells by providing inductive cues. Larger scale studies including prospective, randomized control trials must be performed to determine the optimum cell delivery method and cytokine stimuli for tissue engineering driven strategies to address the clinical needs in skeletal and soft tissue reconstruction.

Before stem cell-based therapies can become a clinical reality, technologies for cell delivery must be developed that can control differentiation and pluripotency, maintain a hospitable environment for cell survival and function, and provide a structural framework for regenerative healing of the target tissue. Insights gained from developmental and stem cell biology should guide the design of devices and techniques to facilitate stem cell-based therapies. Several strategies have been developed for surgical delivery of stem cells, including synthetic and biologic matrices for cell seeding, complex biochemical delivery devices for maintenance and modulation of stem cell properties, and smart constructs with the ability to adapt to the dynamic in vivo environment after implantation. In aggregate, surgical delivery of complex stem cell-seeded constructs has the potential to revolutionize surgical therapies for a wide range of diseases in order to provide a more regenerative platform for tissue and organ healing.

Exuberant fibroproliferation is a common complication after injury for reasons that are not well understood1. One key component of wound repair that is often overlooked is mechanical force, which regulates cell-matrix interactions through intracellular focal adhesion components, including focal adhesion kinase (FAK)1,2. Here we report that FAK is activated after cutaneous injury and that this process is potentiated by mechanical loading. Fibroblast-specific FAK knockout mice have substantially less inflammation and fibrosis than control mice in a model of hypertrophic scar formation. We show that FAK acts through extracellular-related kinase (ERK) to mechanically trigger the secretion of monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), a potent chemokine that is linked to human fibrotic disorders3–5. Similarly, MCP-1 knockout mice form minimal scars, indicating that inflammatory chemokine pathways are a major mechanism by which FAK mechanotransduction induces fibrosis. Small-molecule inhibition of FAK blocks these effects in human cells and reduces scar formation in vivo through attenuated MCP-1 signaling and inflammatory cell recruitment. These findings collectively indicate that physical force regulates fibrosis through inflammatory FAK–ERK–MCP-1 pathways and that molecular strategies targeting FAK can effectively uncouple mechanical force from pathologic scar formation.

Wound repair is a complex biologic process which becomes abnormal in numerous disease states. Althoughin vitromodels have been important in identifying critical repair pathways in specific cell populations,in vivomodels are necessary to obtain a more comprehensive and pertinent understanding of human wound healing. The laboratory mouse has long been the most common animal research tool and numerous transgenic strains and models have been developed to help researchers study the molecular pathways involved in wound repair and regeneration. This paper aims to highlight common surgical mouse models of cutaneous disease and to provide investigators with a better understanding of the benefits and limitations of these models for translational applications.

Wound repair is a complex process involving the orchestrated interaction of multiple growth factors, cytokines, chemokines, and cell types. Dysregulation of this process leads to problems such as excessive healing in the form of keloids and hypertrophic scars and chronic, nonhealing wounds. These issues have broad global implications. Stem cells offer enormous potential for enhancing tissue repair and regeneration following injury. The rapidly developing fields of stem cell biology and skin tissue engineering create translational opportunities for the development of novel stem cell-based wound-healing therapies.

Although numerous factors are implicated in skin fibrosis, the exact pathophysiology of hypertrophic scarring remains unknown. We recently demonstrated that mechanical force initiates hypertrophic scar formation in a murine model, potentially enhancing cellular survival through Akt. Here, we specifically examined Akt-mediated mechanotransduction in fibroblasts using both strain culture systems and our murine scar model. In vitro, static strain increased fibroblast motility, an effect blocked by wortmannin (a phosphoinositide-3-kinase/Akt inhibitor). We also demonstrated that high-frequency cyclic strain was more effective at inducing Akt phosphorylation than low frequency or static strain. In vivo, Akt phosphorylation was induced by mechanical loading of dermal fibroblasts in both unwounded and wounded murine skin. Mechanically loaded scars also exhibited strong expression of α-smooth muscle actin, a putative marker of pathologic scar formation. In vivo inhibition of Akt increased apoptosis but did not significantly abrogate hypertrophic scar development. These data suggest that although Akt signaling is activated in fibroblasts during mechanical loading of skin, this is not the critical pathway in hypertrophic scar formation. Future studies are needed to fully elucidate the critical mechanotransduction components and pathways which activate skin fibrosis.

A thorough understanding of vascular biology will assist the reconstructive surgeon in both operative planning and development of novel surgical approaches to treat chronic wounds and tissue loss, and to optimize regenerative strategies for tissue reconstruction. In this review, several fundamental concepts of the basic science of vascular biology are discussed, with specific emphasis on the clinical implications most relevant to the reconstructive surgeon. Topics include the vascular physiology of tissue flaps and grafts, the principles of neovascularization including angiogenesis and vasculogenesis, and the basic concepts of bioengineering of vascularized tissue constructs for use in reconstruction. As basic science research increases our collective understanding of vascular physiology--specifically, in the areas of neovascularization and tissue engineering--reconstructive surgeons will be able to improve treatment of the sequelae of ischemic injuries, tissue loss, and chronic wounds.

Adipose-derived stromal cells hold promise for use in tissue regeneration. However, multiple facets of their biology remain unclear. The authors examined the variations in osteogenesis and adipogenesis in adipose-derived stromal cells between subcutaneous fat depots and potential molecular causes.Adipose-derived stromal cells were isolated from human patients from subcutaneous fat depots, including arm, flank, thigh, and abdomen (n = 5 patients). Osteogenic and adipogenic differentiation was performed (alkaline phosphatase, alizarin red, and oil red O staining, and quantitative real-time polymerase chain reaction). Co-cultures were established to assess the paracrine effect of human adipose-derived stromal cells on mouse osteoblasts. Finally, HOX gene expression was analyzed by quantitative real-time polymerase chain reaction.Subcutaneous fat depots retain markedly different osteogenic and adipogenic potentials. Osteogenesis was most robust in adipose-derived stromal cells from the flank and thigh, as compared with those from the arm and abdomen (p0.05 by all markers examined). This was accompanied by elevations of BMP4 and BMPR1B (p0.05 by all markers examined). The osteogenic advantage of cells from the flank and thigh was again observed when analyzing the paracrine effects of these cells. Conversely, those cells isolated from the flank had a lesser ability to undergo adipogenic differentiation. Adipose-associated HOX genes were less expressed in flank-derived adipose-derived stromal cells.Variations exist between fat depots in terms of adipose-derived stromal cell osteogenic and adipogenic differentiation. Differences in HOX expression and bone morphogenetic protein signaling may underlie these observations. This study indicates that the choice of fat depot derivation of adipose-derived stromal cells may be an important one for future efforts in tissue engineering.

Diabetic wounds are a significant public health burden, with slow or nonhealing diabetic foot ulcers representing the leading cause of non-traumatic lower limb amputation in developed countries. These wounds heal poorly as a result of compromised blood vessel formation in response to ischemia. We have recently shown that this impairment in neovascularization results from a high glucose-induced defect in transactivation of hypoxia-inducible factor-1alpha (HIF-1alpha), the transcription factor regulating vascular endothelial growth factor (VEGF) expression. HIF-1 dysfunction is the end result of reactive oxygen species-induced modification of its coactivator p300 by the glycolytic metabolite methylglyoxal. Use of the iron chelator-antioxidant deferoxamine (DFO) reversed these effects and normalized healing of humanized diabetic wounds in mice. Here, we present additional data demonstrating that HIF-1alpha activity, not stability, is impaired in the high glucose environment. We demonstrate that high glucose-induced impairments in HIF-1alpha transactivation persist even in the setting of constitutive HIF-1alpha protein overexpression. Further, we show that high glucose-induced hydroxylation of the C-terminal transactivation domain of HIF-1alpha (the primary pathway regulating HIF-1alpha/p300 binding) does not alter HIF-1alpha activity. We extend our study of DFO's therapeutic efficacy in the treatment of impaired wound healing by demonstrating improvements in tissue viability in diabetic mice with DFO-induced increases in VEGF expression and vascular proliferation. Since DFO has been in clinical use for decades, the potential of this drug to treat a variety of ischemic conditions in humans can be evaluated relatively quickly.

In children with pulmonary atresia not amenable to initial complete correction, antegrade pulmonary blood flow can be established with surgical right ventricular outflow tract (RVOT) patch enlargement. An 11-year experience with RVOT transannular patch (TAP) augmentation without the use of cardiopulmonary bypass (off-pump) is reported. From March 1993 to October 2004, off-pump surgical RVOT enlargement with a TAP was attempted in all patients in whom a concurrent procedure that required bypass was not required. The procedure was performed with cardiopulmonary bypass standby. Twenty-two consecutive patients in whom this procedure was attempted were reviewed. Twenty of 22 patients tolerated off-pump TAP placement. In 2 patients with ductal-dependent pulmonary blood flow, off-pump TAP placement was not tolerated. Adequate antegrade pulmonary blood flow was achieved in all patients without operative mortalities or complications. There was one death in the postoperative period from myocardial ischemia secondary to right ventricular-dependent coronary circulation. Transannular RVOT patch augmentation can be performed safely and effectively without cardiopulmonary bypass.

Diabetic vascular pathology is largely attributable to impairments in tissue recovery from hypoxia. Circulating progenitor cells have been postulated to play a role in ischemic recovery, and deficiencies in these cells have been well described in diabetic patients. Here, we examine bone marrow–derived mesenchymal progenitor cells (BM-MPCs) that have previously been shown to be important for new blood vessel formation and demonstrate significant deficits in the context of diabetes. Further, we determine that this dysfunction is attributable to intrinsic defects in diabetic BM-MPCs that are not correctable by restoring glucose homeostasis. We identify two transcriptionally distinct subpopulations that are selectively depleted by both type 1 and type 2 diabetes, and these subpopulations have provasculogenic expression profiles, suggesting that they are vascular progenitor cells. These results suggest that the clinically observed deficits in progenitor cells may be attributable to selective and irreversible depletion of progenitor cell subsets in patients with diabetes.