Mark W. Maxfield

Concise Review: Tissue-Engineered Vascular Grafts for Cardiac Surgery: Past, Present, and Future

In surgical repair for heart or vascular disease, it is often necessary to implant conduits or correct tissue defects. The most commonly used graft materials to date are (a) artificial grafts; (b) autologous tissues, such as pericardium and saphenous vein; (c) allografts; and (d) xenografts. However, none of these four options offer growth potential, and all are associated with varying levels of thrombogenicity and susceptibility to infection. The lack of growth potential of these four options is particularly important in pediatric cardiac surgery, where patients will often outgrow their vascular grafts and require additional operations. Thus, developing a material with sufficient durability and growth potential that will function as the child grows older will eliminate the need for reoperation and significantly reduce morbidity and mortality of some types of congenital heart defects. Vascular tissue engineering is a relatively new field that has undergone enormous growth over the last decade. The goal of vascular tissue engineering is to produce neovessels and neo‐organ tissue from autologous cells using a biodegradable polymer as a scaffold. The most important advantage of tissue‐engineered implants is that these tissues can grow, remodel, rebuild, and respond to injury. Once the seeded autologous cells have deposited an extracellular matrix and the original scaffold is biodegraded, the tissue resembles and behaves as native tissue. When tissue‐engineered vascular grafts are eventually put to use in the clinical arena, the quality of life in patients after surgery will be drastically improved.

Tissue-engineered vascular grafts for use in the treatment of congenital heart disease: from the bench to the clinic and back again.

Since the first tissue-engineered vascular graft (TEVG) was implanted in a child over a decade ago, growth in the field of vascular tissue engineering has been driven by clinical demand for improved vascular prostheses with performance and durability similar to an autologous blood vessel. Great strides were made in pediatric congenital heart surgery using the classical tissue engineering paradigm, and cell seeding of scaffolds in vitro remained the cornerstone of neotissue formation. Our second-generation bone marrow cell-seeded TEVG diverged from tissue engineering dogma with a design that induces the recipient to regenerate vascular tissue in situ. New insights suggest that neovessel development is guided by cell signals derived from both seeded cells and host inflammatory cells that infiltrate the graft. The identification of these signals and the regulatory interactions that influence cell migration, phenotype and extracellular matrix deposition during TEVG remodeling are yielding a next-generation TEVG engineered to guide neotissue regeneration without the use of seeded cells. These developments represent steady progress towards our goal of an off-the-shelf tissue-engineered vascular conduit for pediatric congenital heart surgery.

Multicenter international randomized comparison of objective and subjective outcomes between electronic and traditional chest drainage systems.

BACKGROUND The aim of this study was to assess the impact of digital versus traditional drainage devices on chest tube removal and patient satisfaction. METHODS A randomized trial of digital versus traditional devices after lobectomy/segmentectomy was conducted at 4 international centers (United Kingdom, Europe, Asia, United States). Patients were managed with overnight suction followed by gravity drainage. Chest tubes were removed when an air leak was not evident anymore and the drained fluid was less than 400 mL/d. RESULTS The groups (digital, 191 patients; traditional, 190 patients) were well matched for baseline and surgical characteristics. There were 325 lobectomies/bilobectomies and 56 segmentectomies, 308 of which were performed by video-assisted thoracic surgery (VATS). Patients randomized to digital systems had a significantly shorter air leak duration (1.0 versus 2.2 days; p=0.001), duration of chest tube placement (3.6 versus 4.7 days; p=0.0001), and postoperative length of stay (4.6 versus 5.6 days; p<0.0001). Subjective end points revealed a perceived improved ability to arise from bed (p=0.008), system convenience for patients and personnel (p=0.02), and the potential for being comfortable when discharged home with the device (p=0.06). A mean difference of 2.6 days from air leak cessation to tube removal was observed, which was similar in the 2 groups (p=0.7). Multivariable regression analysis showed that duration of chest tube placement after air leak cessation was directly associated with the amount of fluid drained during the first 48 hours (p=0.01) and the duration of air leak (p=0.008), independent of hospital location. CONCLUSIONS Patients managed with digital drainage systems experienced a shorter duration of chest tube placement, shorter hospital stays, and higher satisfaction scores compared with those managed with traditional devices. ( CLINICAL TRIAL REGISTRATION NUMBER NCT01747889.).

In vivo applications of electrospun tissue-engineered vascular grafts: a review.

There is great clinical demand for synthetic vascular grafts with improved long-term efficacy. The ideal vascular conduit is easily implanted, nonthrombogenic, biocompatible, resists aneurysmal dilatation, and ultimately degrades or is assimilated as the patient remodels the graft into tissue resembling native vessel. The field of vascular tissue engineering offers an opportunity to design the ideal synthetic graft, and researchers have evaluated a variety of methods and materials for use in graft construction. Electrospinning is one method that has received considerable attention within tissue engineering for constructing so-called tissue scaffolds. Tissue scaffolds are temporary, porous structures which are commonly composed of bioresorbable polymers that promote native tissue ingrowth and have degradation kinetics compatible with a patients rate of extracellular matrix production in order to successfully transit from synthetic conduits into neovessels. In this review, we summarize the history of tissue-engineered vascular grafts (TEVG), focusing on scaffolds generated by the electrospinning process, and discuss in vivo applications. We review the materials commonly employed in this approach and the preliminary results after implantation in animal models in order to gauge clinical viability of the electrospinning process for TEVG construction. Scientists have studied electrospinning technology for decades, but only recently has it been orthotopically evaluated in animal models such as TEVG. Advantages of electrospun TEVG include ease of construction, favorable cellular interactions, control of scaffold features such as fiber diameter and pore size, and the ability to choose from a variety of polymers possessing a range of mechanical and chemical properties and degradation kinetics. Given its advantages, electrospinning technology merits investigation for use in TEVG, but an emphasis on long-term in vivo evaluation is required before its role in clinical vascular tissue engineering can be realized.

Tissue engineering of blood vessels in cardiovascular disease: moving towards clinical translation

Tissue engineering focuses on the construction of three-dimensional neotissues from their cellular components. Neotissue can be used to repair or replace tissues that are missing, damaged, or diseased. Despite its relative youth, the field has undergone significant growth. Vascular tissue engineering is at the forefront in the translation of this technology, as tissue engineered vascular grafts have already been successfully implanted in children with congenital heart disease. The purpose of this report is to review the advances in the understanding of tissue engineered vascular grafts as the technology moves to clinical translation.

Evaluation of remodeling process in small-diameter cell-free tissue-engineered arterial graft

OBJECTIVE Autologous grafts are used to repair atherosclerotic cardiovascular diseases; however, many patients lack suitable donor graft tissue. Recently, tissue engineering techniques have emerged to make biologically active blood vessels. We applied this technique to produce arterial grafts using established biodegradable materials without cell seeding. The grafts were evaluated in vivo for vessel remodeling during 12 months. METHODS Poly(L-lactide-co-ε-caprolactone) scaffolds reinforced by poly(lactic acid) (PLA) fiber were prepared as arterial grafts. Twenty-eight cell-free grafts were implanted as infrarenal aortic interposition grafts in 8-week-old female SCID/Bg mice. Serial ultrasound and micro computed tomography angiography were used to monitor grafts after implantation. Five grafts were harvested for histologic assessments and reverse transcription-quantitative polymerase chain reaction analysis at time points ranging from 4 months to 1 year after implantation. RESULTS Micro computed tomography indicated that most implanted mice displayed aneurysmal changes (three of five mice at 4 months, four of five mice at 8 months, and two of five mice at 12 months). Histologic assessments demonstrated extensive tissue remodeling leading to the development of well-circumscribed neovessels with an endothelial inner lining, a neointima containing smooth muscle cells and elastin, and a collagen-rich extracellular matrix. There were a few observed calcified deposits, located around residual PLA fibers at 12 months after implantation. Macrophage infiltration into the scaffold, as evaluated by F4/80 immunohistochemical staining, remained after 12 months and was focused mostly around residual PLA fibers. Reverse transcription-quantitative polymerase chain reaction analysis revealed that gene expression of Itgam, a marker for macrophages, and of matrix metalloproteinase 9 was higher than in native aorta during the course of 12 months, indicating prolonged inflammation (Itgam at 8 months: 11.75 ± 0.99 vs native aorta, P < .01; matrix metalloproteinase 9 at 4 months: 4.35 ± 3.05 vs native aorta, P < .05). CONCLUSIONS In this study, we demonstrated well-organized neotissue of cell-free biodegradable arterial grafts. Although most grafts experienced aneurysmal change, such findings provide insight into the process of tissue-engineered vascular graft remodeling and should allow informed rational design of the next generation of arterial grafts.

Well-organized neointima of large-pore poly(l-lactic acid) vascular graft coated with poly(l-lactic-co-ε-caprolactone) prevents calcific deposition compared to small-pore electrospun poly(l-lactic acid) graft in a mouse aortic implantation model

OBJECTIVE Tissue engineering techniques have emerged that allow bioresorbable grafts to be implanted that restore function and transform into biologically active arteries. However, these implants are susceptible to calcification during the remodeling process. The objective of this study was to evaluate the role of pore size of bioabsorbable grafts in the development of calcification. METHODS Two types of grafts were prepared: a large-pore graft constructed of poly(L-lactic acid) (PLA) fibers coated with poly(L-lactide-co-ε-caprolactone) (PLCL) (PLA-PLCL), and a small-pore graft made of electrospun PLA nanofibers (PLA-nano). Twenty-eight PLA-PLCL grafts and twenty-five PLA-nano grafts were implanted as infra-renal aortic interposition conduits in 8-week-old female SCID/Bg mice, and followed for 12 months after implantation. RESULTS Large-pore PLA-PLCL grafts induced a well-organized neointima after 12 months, and Alizarin Red S staining showed neointimal calcification only in the thin neointima of small-pore PLA-nano grafts. At 12 months, macrophage infiltration, evaluated by F4/80 staining, was observed in the thin neointima of the PLA-nano graft, and there were few vascular smooth muscle cells (VSMCs) in this layer. On the other hand, the neointima of the PLA-PLCL graft was composed of abundant VSMCs, and a lower density of macrophages (F4/80 positive cells, PLA-PLCL; 68.1 ± 41.4/mm(2) vs PLA-nano; 188.3 ± 41.9/mm(2), p = 0.007). The VSMCs of PLA-PLCL graft expressed transcription factors of both osteoblasts and osteoclasts. CONCLUSION These findings demonstrate that in mouse arterial circulation, large-pore PLA-PLCL grafts created a well-organized neointima and prevented calcific deposition compared to small-pore, electrospun PLA-nano grafts.

Development of small diameter nanofiber tissue engineered arterial grafts.

The surgical repair of heart and vascular disease often requires implanting synthetic grafts. While synthetic grafts have been successfully used for medium-to-large sized arteries, applications for small diameter arteries (<6 mm) is limited due to high rates of occlusion by thrombosis. Our objective was to develop a tissue engineered vascular graft (TEVG) for small diameter arteries. TEVGs composed of polylactic acid nanofibers with inner luminal diameter between 0.5 and 0.6 mm were surgically implanted as infra-renal aortic interposition conduits in 25 female C17SCID/bg mice. Twelve mice were given sham operations. Survival of mice with TEVG grafts was 91.6% at 12 months post-implantation (sham group: 83.3%). No instances of graft stenosis or aneurysmal dilatation were observed over 12 months post-implantation, assessed by Doppler ultrasound and microCT. Histologic analysis of explanted TEVG grafts showed presence of CD31-positive endothelial monolayer and F4/80-positive macrophages after 4, 8, and 12 months in vivo. Cells positive for α-smooth muscle actin were observed within TEVG, demonstrating presence of smooth muscle cells (SMCs). Neo-extracellular matrix consisting mostly of collagen types I and III were observed at 12 months post-implantation. PCR analysis supports histological observations. TEVG group showed significant increases in expressions of SMC marker, collagen-I and III, matrix metalloproteinases-2 and 9, and itgam (a macrophage marker), when compared to sham group. Overall, patency rates were excellent at 12 months after implantation, as structural integrity of these TEVG. Tissue analysis also demonstrated vessel remodeling by autologous cell.

Tissue engineering in the vasculature.

Tissue engineering holds great promise to address complications and limitations encountered with the use of traditional prosthetic materials, such as thrombogenicity, infection, and future degeneration which represent the major morbidity and mortality after device implant surgery. The general concept of tissue engineering consists of three main components: a scaffold material, a cell type for seeding the scaffold, and biochemical, physio‐chemical signaling and remodeling process. This remodeling process is guided by cell signals derived from both seeded cells and host inflammatory cells that infiltrate the scaffold and deposit extracellular matrix, forming the neotissue. Vascular tissue engineering is at the forefront in the translation of this technology to clinical practice, as tissue engineered vascular grafts (TEVGs) have now been successfully implanted in children with congenital heart disease. In this report, we review the history, advances, and state of the art in TEVGs. Anat Rec, 297:83–97. 2014.

Impact of adaptive statistical iterative reconstruction on radiation dose in evaluation of trauma patients

BACKGROUND A recent study showed that computed tomographic (CT) scans contributed 93% of radiation exposure of 177 patients admitted to our Level I trauma center. Adaptive statistical iterative reconstruction (ASIR) is an algorithm that reduces the noise level in reconstructed images and therefore allows the use of less ionizing radiation during CT scans without significantly affecting image quality. ASIR was instituted on all CT scans performed on trauma patients in June 2009. Our objective was to determine if implementation of ASIR reduced radiation dose without compromising patient outcomes. METHODS We identified 300 patients activating the trauma system before and after the implementation of ASIR imaging. After applying inclusion criteria, 245 charts were reviewed. Baseline demographics, presenting characteristics, number of delayed diagnoses, and missed injuries were recorded. The postexamination volume CT dose index (CTDIvol) and dose-length product (DLP) reported by the scanner for CT scans of the chest, abdomen, and pelvis and CT scans of the brain and cervical spine were recorded. Subjective image quality was compared between the two groups. RESULTS For CT scans of the chest, abdomen, and pelvis, the mean CTDIvol (17.1 mGy vs. 14.2 mGy; p < 0.001) and DLP (1,165 mGy·cm vs. 1,004 mGy·cm; p < 0.001) was lower for studies performed with ASIR. For CT scans of the brain and cervical spine, the mean CTDIvol (61.7 mGy vs. 49.6 mGy; p < 0.001) and DLP (1,327 mGy·cm vs. 1,067 mGy·cm; p < 0.001) was lower for studies performed with ASIR. There was no subjective difference in image quality between ASIR and non-ASIR scans. All CT scans were deemed of good or excellent image quality. There were no delayed diagnoses or missed injuries related to CT scanning identified in either group. CONCLUSION Implementation of ASIR imaging for CT scans performed on trauma patients led to a nearly 20% reduction in ionizing radiation without compromising outcomes or image quality. LEVEL OF EVIDENCE Therapeutic study, level IV.