Development of tissue-engineered tracheal scaffold with refined mechanical properties and vascularisation for tracheal regeneration.

Introduction: Attempted tracheal replacement efforts thus far have had very little success. Major limiting factors have been the inability to efficiently re-vascularise and mimic the mechanical properties of native tissue. The major objective of this study was to optimise a previously developed collagen-hyaluronic acid scaffold (CHyA-B), which has shown to facilitate the growth of respiratory cells in distinct regions, as a potential tracheal replacement device. Methods: A biodegradable thermoplastic polymer was 3D-printed into different designs and underwent multi-modal mechanical assessment. The 3D-printed constructs were incorporated into the CHyA-B scaffolds and subjected to in vitro and ex vivo vascularisation. Results: The polymeric backbone provided sufficient strength to the CHyA-B scaffold, with yield loads of 1.31-5.17 N/mm and flexural moduli of 0.13-0.26 MPa. Angiogenic growth factor release (VEGF and bFGF) and angiogenic gene upregulation (KDR, TEK-2 and ANG-1) was detected in composite scaffolds and remained sustainable up to 14 days. Confocal microscopy and histological sectioning confirmed the presence of infiltrating blood vessel throughout composite scaffolds both in vitro and ex vivo. Discussion: By addressing both the mechanical and physiological requirements of tracheal scaffolds, this work has begun to pave the way for a new therapeutic option for large tracheal defects.

Engineering Large Airways.

A key issue facing trachea replacement attempts has been the discrepancy of the mechanical properties between the native tracheal tissue and that of the replacement construct; this difference is often one of the major causes for implant failure in vivo and within clinical efforts. The trachea is composed of distinct structural regions, with each component fulfilling a different role in maintaining overall tracheal stability. The trachea's horseshoe-shaped hyaline cartilage rings, smooth muscle and annular ligament collectively produce an anisotropic tissue that allows for longitudinal extensibility and lateral rigidity. Therefore, any tracheal substitute must be mechanically robust in order to withstand intra-thoracic pressure changes that occur during respiration. Conversely, they must also be able to deform radially to allow for changes in the cross-sectional area during coughing and swallowing. These complicated native tissue characteristics, coupled with a lack of standardised protocols to accurately quantify tracheal biomechanics as guidance for implant design, constitute a significant hurdle for tracheal biomaterial scaffold fabrication. This chapter aims to highlight the pressure forces exerted on the trachea and how they can influence tracheal construct design and also the biomechanical properties of the three main components of the trachea and how to mechanically assess them.

Update on Wearable Cardioverter Defibrillator: A Comprehensive Review of Literature.

Despite the advancements in the prevention and treatment of cardiovascular diseases, sudden cardiac death (SCD) remains a leading cause of mortality and is accountable for approximately 15% of the total mortality in the USA. The prognosis after sudden cardiac arrest (SCA) varies significantly and depends largely on the underlying etiology and the rapidity and efficiency of resuscitation; however, the outcome remains poor for most of the patients. The main culprits for SCD are coronary heart disease (CHD) and heart failure with reduced ejection fraction (HFrEF). Patients with HFrEF and an ejection fraction (EF) of less than 35% are considered for an implantable cardioverter-defibrillator (ICD) placement if the EF does not improve. A wearable cardioverter defibrillator (WCD) commonly known as a life-vest is sometimes used as a bridging modality until an ICD is implanted. The indication and utility of WCD is still a controversial topic. The purpose of this article is to provide an up-to-date comprehensive review of literature for WCD utilization.

Development and clinical translation of tubular constructs for tracheal tissue engineering: a review.

Effective restoration of extensive tracheal damage arising from cancer, stenosis, infection or congenital abnormalities remains an unmet clinical need in respiratory medicine. The trachea is a 10-11 cm long fibrocartilaginous tube of the lower respiratory tract, with 16-20 tracheal cartilages anterolaterally and a dynamic trachealis muscle posteriorly. Tracheal resection is commonly offered to patients suffering from short-length tracheal defects, but replacement is required when the trauma exceeds 50% of total length of the trachea in adults and 30% in children. Recently, tissue engineering (TE) has shown promise to fabricate biocompatible tissue-engineered tracheal implants for tracheal replacement and regeneration. However, its widespread use is hampered by inadequate re-epithelialisation, poor mechanical properties, insufficient revascularisation and unsatisfactory durability, leading to little success in the clinical use of tissue-engineered tracheal implants to date. Here, we describe in detail the historical attempts and the lessons learned for tracheal TE approaches by contextualising the clinical needs and essential requirements for a functional tracheal graft. TE manufacturing approaches explored to date and the clinical translation of both TE and non-TE strategies for tracheal regeneration are summarised to fully understand the big picture of tracheal TE and its impact on clinical treatment of extensive tracheal defects.

A Tissue-Engineered Tracheobronchial In Vitro Co-Culture Model for Determining Epithelial Toxicological and Inflammatory Responses.

Translation of novel inhalable therapies for respiratory diseases is hampered due to the lack of in vitro cell models that reflect the complexity of native tissue, resulting in many novel drugs and formulations failing to progress beyond preclinical assessments. The development of physiologically-representative tracheobronchial tissue analogues has the potential to improve the translation of new treatments by more accurately reflecting in vivo respiratory pharmacological and toxicological responses. Herein, advanced tissue-engineered collagen hyaluronic acid bilayered scaffolds (CHyA-B) previously developed within our group were used to evaluate bacterial and drug-induced toxicity and inflammation for the first time. Calu-3 bronchial epithelial cells and Wi38 lung fibroblasts were grown on either CHyA-B scaffolds (3D) or Transwell® inserts (2D) under air liquid interface (ALI) conditions. Toxicological and inflammatory responses from epithelial monocultures and co-cultures grown in 2D or 3D were compared, using lipopolysaccharide (LPS) and bleomycin challenges to induce bacterial and drug responses in vitro. The 3D in vitro model exhibited significant epithelial barrier formation that was maintained upon introduction of co-culture conditions. Barrier integrity showed differential recovery in CHyA-B and Transwell® epithelial cultures. Basolateral secretion of pro-inflammatory cytokines to bacterial challenge was found to be higher from cells grown in 3D compared to 2D. In addition, higher cytotoxicity and increased basolateral levels of cytokines were detected when epithelial cultures grown in 3D were challenged with bleomycin. CHyA-B scaffolds support the growth and differentiation of bronchial epithelial cells in a 3D co-culture model with different transepithelial resistance in comparison to the same co-cultures grown on Transwell® inserts. Epithelial cultures in an extracellular matrix like environment show distinct responses in cytokine release and metabolic activity compared to 2D polarised models, which better mimic in vivo response to toxic and inflammatory stimuli offering an innovative in vitro platform for respiratory drug development.

Automatic Referral for Potential Thoracic Malignant Diseases Detected on Computed Tomographic Scan.

BACKGROUND: Delays in care negatively affect patients with potentially resectable thoracic malignant diseases. The Alberta Thoracic Oncology Program established an automatic referral process for patients with chest computed tomographic (CT) scans suggestive of malignant disease. The objective of this study was to determine whether automatic referral was associated with decreased time to referral or differences in the quality of referral information received. METHODS: A single-center retrospective review of patients referred to a Canadian tertiary thoracic surgical center was performed. The time between the CT scan and the date of referral was calculated, and the type of information provided with the referral was tabulated. Automatic and traditional referral groups were compared using the Student t test, the Mann-Whitney U test, and multivariable analysis. RESULTS: A total of 689 patients met inclusion criteria, and 405 of these patients were automatic referrals. Average time to referral was shorter in the automatic referral group (4.7 days vs 23.6 days; P < .001). Only 2 automatic referrals took longer than 30 days, compared with more than 25% of traditional referrals. Automatic referrals were always associated with a shorter time for referral on subgroup analysis of lung nodules, different referring physician types, and patient location. There was no difference between referral types in the number of referral data provided to the center. CONCLUSIONS: Automatic referrals for patients with potential thoracic malignant disease have a significant beneficial impact on delays in care, and this could result in improved outcomes, such as decreased upstaging and improved survival. This was not associated with a decrease in the amount of information provided with the referral. Thus, automatic referrals may streamline patient care without compromising quality.

Core Measures for Congestive Heart Failure in a Tertiary Care Setting in Pakistan.

PURPOSE:  Heart failure presents a huge burden for individual patients and the healthcare system as a whole. This study aims to assess the adherence to these core measures as identified by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO)/ American Heart Association (AHA) by physicians of Pakistan. MATERIALS AND METHODOLOGY:  We conducted a cross-sectional study in Shifa International Hospital, Islamabad, Pakistan from the period of April 2013 to April 2016. Patients with a primary diagnosis of heart failure were drawn from a coding section of hospital's record department. Data was evaluated to assess how strictly doctors were following core measures identified by JCAHO/AHA for the given diagnosis. Inclusion criteria for this study were patients ≥ 17 years of age and patients with a primary diagnosis of heart failure according to New York Heart Association (NYHA) classification. Patients with congenital anomalies and structural heart wall problems, like sarcoidosis, hemochromatosis, and amyloidosis, were excluded from the study. RESULTS:  Mean ejection fraction (EF) was found to be 27.23 ± 11.72 percent. Symptoms assessment of heart failure was done in 16/421 (3.8%) patients according to NYHA classification and in 405/421 (96.2%) patients according to outpatient-based heart failure assessment based on physician's experience other than NYHA classification. Left ventricle ejection fraction (LVEF) was assessed in 411/421 (97%) patients. Out of these, 336/411 (81.7%) patients had EF < 40%. Mean EF was found to be significantly higher in females as compared to males (p < 0.001). Three hundred and thirty-six out of 411 (81.7%) patients with EF < 40% needed angiotensin converting enzyme inhibitors (ACEi) and beta-blocker (BB) prescriptions. ACEi were prescribed only to 230/336 (68.7%) patients and 248/336 (73.8%) patients were given BB with documented contraindication to ACEi and BB in 7.36% and 17% patients, respectively. There was no significant association between gender and mean duration of hospitalization (p = 0.411). No significant association was found between EF ≤ 40% and mean duration of hospitalization (p = 0.426). CONCLUSION:  We found that symptom assessment of congestive heart failure (CHF) patients, according to NYHA guidelines, are strikingly low. Also, a significant percentage of patients who need ACEi and BB are not prescribed the required medications despite echocardiography showing low left ventricular function.