Harald C. Ott's research while affiliated with Harvard University and other places

Publications (72)

Article
Lung transplantation remains the only curative treatment for end stage pulmonary disease. Lung ischemia-reperfusion injury (IRI) is a major contributor to primary allograft dysfunction and donor organ non-utilization. The alveolar macrophage is a key inflammatory mediator in IRI. Ex vivo lung perfusion (EVLP) has been investigated to rehabilitate l...
Article
The catastrophic global effects of the SARS-CoV-2 pandemic highlight the need to develop novel therapeutics strategies to prevent and treat viral infections of the respiratory tract. To enable this work, we need scalable, affordable, and physiologically relevant models of the human lung, the primary organ involved in the pathogenesis of COVID-19. T...
Article
Purpose: To assess the technical success and complication rates of CT-guided fiducial marker placement for the localization of pulmonary nodules and to assess the surgical localization failure rate. Materials and methods: This was a single-center, retrospective analysis of consecutive patients who underwent CT-guided fiducial marker placement pr...
Article
Lung regeneration is dependent on the availability of progenitor lung cells. Large numbers of self-renewing, patient-specific induced pluripotent stem cell derived alveolar epithelial cells (iPSC-AECs) are needed to adequately recellularize whole organ constructs. Prior methods to generated functional iPSC-AECs are not feasible for large-scale cell...
Article
Full-text available
Epicardial formation is necessary for normal myocardial morphogenesis. Here, we show that differentiating hiPSC-derived lateral plate mesoderm with BMP4, RA and VEGF (BVR) can generate a premature form of epicardial cells (termed pre-epicardial cells, PECs) expressing WT1 , TBX18 , SEMA3D , and SCX within 7 days. BVR stimulation after Wnt inhibitio...
Article
Rationale: Early, accurate diagnosis of interstitial lung disease (ILD) informs prognosis and therapy, especially in idiopathic pulmonary fibrosis (IPF). Current diagnostic methods are imperfect. HRCT resolution is limited while surgical lung biopsy (SLB) carries risks of morbidity/mortality. Endobronchial optical coherence tomography (EB-OCT) is...
Article
Background: Esophageal perforation is a morbid condition and remains a therapeutic challenge. We report the outcomes of a large institutional experience with esophageal perforation and identify risk factors for morbidity and mortality. Methods: A retrospective analysis was conducted on 142 patients who presented with a thoracic or gastroesophage...
Article
Purpose Lung transplantation is the only curative treatment for patients with end stage pulmonary disease. The ex vivo reconditioning of lungs deemed unsuitable for transplant could expand the lung donor pool and increase the availability of this life saving treatment. Ischemia-reperfusion injury (IRI) leading to allograft dysfunction is a major co...
Article
Purpose Induced pluripotent stem cell derived alveolar epithelial cells (iPSC-AECs) are a patient specific cell source for bio-engineering of human pulmonary epithelium. Disease modeling and therapeutic applications require cost effective and technically feasible differentiation and expansion protocols. Current culture protocols are labor and resou...
Article
Lung transplantation is the only treatment for end-stage lung disease; however, donor organ shortage and intense immunosuppression limit its broad clinical impact. Bioengineering of lungs with patient-derived cells could overcome these problems. We created bioartificial lungs by seeding human-derived cells onto porcine lung matrices and performed o...
Article
Background Airway release (AR) maneuvers performed during airway resection to reduce anastomotic tension have not been thoroughly studied. Methods We retrospectively analyzed consecutive resections for postintubation stenosis (PITS) and primary tracheal neoplasms (PTN) at a tertiary care center. Anastomotic complications were defined as stenosis,...
Article
Background Approximately 10-15% of patients with solitary fibrous tumors of the pleura (SFTP) recur after resection. Many are not candidates for re-resection and lack effective treatments. We explored the expression of PD-L1 as a biomarker for candidacy for treatment with immune checkpoint inhibitors. Methods Review of medical records of 52 patien...
Article
Objectives: Emphysema affects millions of patients worldwide. Cell transplantation and tissue engineering are promising approaches for the regeneration of gas exchange tissue in vivo. A reproducible and resource-efficient animal model with relevant pathological and physiological features is critical to assess efficacy of novel therapies. Here, we...
Chapter
The human trachea is a vital structure with complex architecture and well-defined mechanical properties. Trauma, neoplasm, congenital defects and iatrogenic injury can lead to loss of patency and necessitate surgical intervention to reestablish its function as a viable and disease resistant airway. Due to the trachea’s structural redundancy, and lo...
Article
e21026 Background: Comprehensive molecular profiling and the use of biomarkers as companion diagnostics have transformed precision medicine for cancer patients. To identify patient-specific tumor microenvironment and biomarker profiles, we assessed the accuracy of our deconvolution algorithm in identifying cellular compositions from whole exome (WE...
Article
Full-text available
Lung transplantation is currently the only curative treatment for patients with end-stage lung disease; however, donor organ shortage and the need for intense immunosuppression limit its broad clinical application. Bioartificial lungs created by combining native matrix scaffolds with patient-derived cells might overcome these problems. Decellulariz...
Article
393 Background: Nearly half of patients with G/GE cancer do not receive or complete post-operative chemotherapy and/or chemoradiation (CRT). Total neoadjuvant therapy (TNT) is as an emerging alternate treatment strategy. We have previously reported a 28% pCR with FOLFIRINOX followed by CRT. However, TNT outcomes with FLOT or FOLFOX followed by CRT...
Article
Current reconstruction methods of the laryngotracheal segment fail to replace the complex functions of the human larynx. Bioengineering approaches to reconstruction have been limited by the complex tissue compartmentation of the larynx. We attempted to overcome this limitation by bio-engineering laryngeal grafts from decellularized canine laryngeal...
Article
Video-assisted thoracic surgery (VATS) and robotically assisted surgery are used increasingly for minimally invasive diagnostic and therapeutic resection of pulmonary nodules. Unsuccessful localization of small, impalpable, or deep pulmonary nodules can necessitate conversion from VATS to open thoracotomy. Preoperative localization techniques perfo...
Article
Background: Complete resection of central tumors invading the main pulmonary artery (PA) requires arterial reconstruction to avoid pneumonectomy. Oncologic equivalence with pneumonectomy has been suggested. We review clinical selection and outcome for these uncommon procedures in the context of candidacy for pneumonectomy. Methods: From 2000 to...
Article
Background: To evaluate the management, complications of treatment, and outcomes of postintubation tracheal stenosis. Methods: A retrospective review was performed of records from a prospective database of all patients undergoing tracheal or laryngotracheal resection from 1993 to 2017 for postintubation tracheal stenosis. Redo operations after f...
Article
Islet transplantation is superior to extrinsic insulin supplementation in the treating severe Type 1 diabetes. However, its efficiency and longevity are limited by substantial islet loss post-transplantation due to lack of engraftment and vascular supply. To overcome these limitations, we developed a novel approach to bio-fabricate functional, vasc...
Article
Full-text available
Purpose: Thoracic air leaks are a common complication following pulmonary resections. Limitations in clinical studies and preclinical models have hindered efforts to understand the pathophysiology of air leaks. With an emphasis on staple-line specific air leaks, we hypothesize that ventilation modality - intraoperative positive pressure vs postope...
Article
Objectives: Complete resection of neoplasms involving the carina are technically challenging and have high operative morbidity and mortality. This study examines the last 2 decades of clinical experience at our institution. Methods: Medical records were retrospectively reviewed between 1997 and 2017 to identify all patients who underwent carinal...
Article
Context.—: Lesion localization during intraoperative frozen section of lung resection specimens can be challenging. Imaging could aid lesion localization while enabling 3-dimensional specimen analysis. Objective.—: To assess the feasibility of integrating micro-computed tomography (micro-CT) into the perioperative evaluation of fresh surgical lu...
Article
Objectives: Many patients with primary malignant tracheal neoplasms are not surgical candidates nor do they experience residual or recurrent disease after surgery and may benefit from alternative therapies. This study explores the expression of programmed death ligand 1 (PD-L1) in patients with primary tracheal malignancy as a biomarker for candid...
Article
Impact statement: This work presents methods for ex vivo lung recellularization and biomimetic culture in a high-throughput and consistent manner. These methods allow for the testing of multiple variables, all of which are simultaneously controlled and monitored on a single fully automated pump system, and subsequent assessment of both epithelial...
Article
Full-text available
Purpose of Review Engineering endocrine pancreatic tissue is an emerging topic in type 1 diabetes with the intent to overcome the current limitation of β cell transplantation. During islet isolation, the vascularized structure and surrounding extracellular matrix (ECM) are completely disrupted. Once implanted, islets slowly engraft and mostly are l...
Article
Decellularized native extracellular matrix (ECM) biomaterials are widely used in tissue engineering and have reached clinical application as biomesh implants. To enhance their regenerative properties and postimplantation performance, ECM biomaterials could be functionalized via immobilization of bioactive molecules. To facilitate ECM functionalizat...
Data
Pax7-CreER;Rosa26-LSL-EYFP iMPCs derived from explanted muscles of tamoxifen-treated Pax7-CreER;Rosa26-LSL-EYFP mouse. Note EYFP expression in mononucleated and multinucleated cells.
Data
Pax7-CreER;Rosa26-LSL-EYFP iMPCs (passage 16) cultured in F/R/G conditions and labeled with 4OHT between passages 5 and 16. Note EYFP expression in mononucleated and multinucleated cells.
Article
Full-text available
Skeletal muscle harbors quiescent stem cells termed satellite cells and proliferative progenitors termed myoblasts, which play pivotal roles during muscle regeneration. However, current technology does not allow permanent capture of these cell populations in vitro. Here, we show that ectopic expression of the myogenic transcription factor MyoD, com...
Article
In reconstructive surgery, transfer of patients' tissue (autologous flaps) is routinely used to repair large soft tissue defects caused by surgery, trauma, chronic diseases, or malformations; unfortunately, this strategy is not always possible and often creates a secondary defect in the donor site of the tissue. Tissue-engineered synthetic flaps ar...
Article
Objective: A novel ex vivo model is described to advance the understanding of prolonged air leaks, one of the most common post-operative complications following thoracic resection procedures. Methods: As an alternative to in vivo testing, an ex vivo model simulating the various physiologic environments experienced by an isolated lung during the...
Article
Background: Tracheal substitutes remain an active area of research. For rare patients with large or complex defects that cannot be repaired primarily, replacement of the airway may represent the only treatment option. The present systematic review aims to assess the clinical successes and setbacks of current methods of airway replacement. Methods...
Article
Aerodigestive defects involving the trachea, bronchi and esophagus are a result of prolonged intubation, operative complications, congenital defects, trauma, radiation and neoplastic disease. The vast majority of these defects may be repaired primarily. Rarely, due the size of the defect, underlying complexity, or unfavorable patient characteristic...
Article
Full-text available
Muscle and fasciocutaneous flaps taken from autologous donor sites are currently the most utilized approach for trauma repair, accounting annually for 4.5 million procedures in the US alone. However, the donor tissue size is limited and the complications related to these surgical techniques lead to morbidities, often involving the donor sites. Alte...
Article
Full-text available
Patients with short bowel syndrome lack sufficient functional intestine to sustain themselves with enteral intake alone. Transplantable vascularized bioengineered intestine could restore nutrient absorption. Here we report the engineering of humanized intestinal grafts by repopulating decellularized rat intestinal matrix with human induced pluripot...
Article
Full-text available
Purpose of Review The purposes of this study were to review current progress being made in engineering bioartificial lungs for transplantation and identify tangible benefits to the implementation of this research into development of 4D lung models for disease modeling, drug screening, and personalized medicine that could be realized in the next 5 y...
Article
Organ engineering based on native matrix scaffolds involves combining regenerative cell populations with corresponding biological matrices to form functional grafts on-demand. The extracellular matrix (ECM) that is retained following lung decellularization provides essential structure and biophysical cues for whole organ regeneration after recellul...
Article
Full thickness skin loss is a challenging problem due to limited reconstructive options, demanding 75 million surgical procedures annually in the United States. Autologous skin grafting is the gold standard treatment, but results in donor site morbidity and poor aesthetics. Numerous skin substitutes are available on the market to date, however, non...
Article
Extracorporeal cross-circulation between lungs enables the extended support of recipient lungs and the recovery of injured lungs in a swine model.
Article
Objective: Bioengineering of viable, functional, and implantable human lung grafts on porcine matrix. Summary background data: Implantable bioartificial organ grafts could revolutionize transplant surgery. To date, several milestones toward that goal have been achieved in rodent models. To make bioengineered organ grafts clinically relevant, sca...
Article
Bio-engineered organs for transplantation may ultimately provide a personalized solution for end-stage organ failure, without the risk of rejection. Building upon the process of whole organ perfusion decellularization, we aimed to develop novel, translational methods for the recellularization and regeneration of transplantable lung constructs. We f...
Article
The University of Vermont College of Medicine, in collaboration with the NHLBI, Alpha-1 Foundation, American Thoracic Society, Cystic Fibrosis Foundation, European Respiratory Society, International Society for Cellular Therapy, and the Pulmonary Fibrosis Foundation, convened a workshop, "Stem Cells and Cell Therapies in Lung Biology and Lung Disea...
Article
In this issue of Transplantation Andrea Peloso and colleagues report on the successful application of perfusion decellularization in discarded human kidneys to generate scaffolds for organ regeneration. (1) The authors provide important insight into mechanical integrity and morphological features of the native vascular tree and examine matrix bound...
Article
Background: Heart valve disease afflicts individuals of all ages, but current treatments, involving replacement with non-viable prosthetics, are particularly suboptimal for young patients. To design “growing” valve replacements, postnatal growth mechanisms must be elucidated; models of adaptive growth are lacking, thereby hindering these investigat...
Article
Purpose of review: Allogeneic organ transplantation is burdened by donor shortage, graft rejection and adverse effects of lifelong immune suppression. Engineering bioartificial organs from acellular organ scaffolds and patient-derived cells are a new approach to potentially overcome these limitations. Recent findings: Decellularized organs yield...

Citations

... (9) This fact should be viewed with concern, given the possibility of development of a similar pattern of bronchiolitis obliterans among individuals with chronic exposure to e-cigarette aerosols of solutions containing flavoring agents. (10,11) AUTHOR CONTRIBUTIONS GCA: study conception; data collection; and drafting of the manuscript. RFM: manuscript revision. ...
... Technical details of the EB-OCT system and methods used in this study have been described previously in detail (4-5, 7-9, 14, 15). A custom PS-EB-OCT system (center wavelength, 1,310 nm; axial resolution, 6 μm) was used in conjunction with a bronchoscope-compatible, flexible catheter (diameter, 1.65 mm) to acquire volumetric datasets of cross-sectional images (image-to-image spacing, 33 μm) in the peripheral subpleural lung from multiple locations in the upper, middle, and lower lobes as previously described (5,16). All patients gave written informed consent for study participation. ...
... A systematic review and meta-analysis of hookwire, microcoil and lipiodol nodule localization techniques found microcoil and lipiodol to have the highest (97-99%) successful localization rates with microcoils having the best safety profile. 100 Fiducial marker placement using gold seeds has similar success rates, but vascular embolization has been reported, 101 while microcoil shape and haemostatic fibre coating eliminate this possibility due to promotion of thrombosis. 97 Long-term outcomes and disease-free survival have also been excellent with the microcoil technique. ...
... Therefore, EMOs represent a reliable tool to recreate the early stages of PE-myocardium interaction, particularly the WT1 + cell arrangement over the myocardium-like layer, opening a clear path to study and model epicardial-myocardial interactions in vitro. Although recent reports have shown evidences for the importance and the positive impact of co-culturing hPSC-CMs with PE cells to obtain more mature and adult-like cardiac models 42,43,67 , only two recent reports established heart organoid models that incorporate epicardial cells 13 . However, none of them showed 1) a well-defined selforganized layer of epicardium surrounding the a CM region in a 3D environment, as it is possible to observe in our EMOs, nor 2) clearly demonstrated the direct impact of epicardial cells on myocardial-like tissue organization and maturation, as it was showed here, supporting the increased relevance of the presented heart organoids. ...
... La OCT se realiza con una fuente de luz rotativa en el infrarrojo cercano y proporciona imágenes sobre un área de 5.4 cm del espacio alveolar y las vías respiratorias, con una profundidad de aproximadamente 2-3 mm y una resolución de 10-15 μm [22,23]. Recientemente se demostró que la OCT distingue con precisión la neumonía intersticial habitual (usual interstitial pneumonia, UIP) de la neumonía intersticial fibrótica inespecífica (fibrotic nonspecific interstitial pneumonia, fNSIP) y de la fibrosis centra-da en las vías respiratorias, al visualizar características fibróticas específicas [24] y correlacionar sus hallazgos con la histología de las biopsias pulmonares. Las imágenes por OCT en la fNSIP mostraron un engrosamiento fibrótico homogéneo de las paredes alveolares intersticiales, mientras que en la UIP se encontraron quistes alveolares microscópicos y una fibrosis subpleural densa y destructiva en las imágenes por OCT. ...
... between the perforation occurring and initiation of treatment is generally considered to be the most important factor that determines morbidity and mortality [2][3][4][5]. ...
... In turn, the global medical community continues accumulating clinical background, studying the features of diagnosis and perioperative management of patients with causative respiratory pathologies after suffering COVID-19 associated pneumonia. This also applies to CTS and tracheoesophageal fistula (TEF) due to prolonged mechanical ventilation using an orotracheal/tracheostomy tube amid severe conditions [15][16][17][18][19][20][21]. ...
... This regenerated endothelium must be able to ensure a correct physiological interaction between blood cells and platelets, as well as coagulation, adhesion, and aggregation factors which are involved in the coagulation process (Furie and Furie, 1988), in order to restore a long-term perfusable non-thrombogenic vascular bed without edema formation in the scaffold, thus providing oxygen and nutrient supplies to the seeded cells. Despite high efficiency and almost total in vitro endothelium restoration in acellular organs showing a physiological vascular flow several days after vascular anastomosis (Uygun et al., 2010;Ren et al., 2015;Hussein et al., 2016;Higashi et al., 2022), this did not prevent significant vascular thrombosis or edema formation from occurring owing to barrier leakiness into the implanted regenerated graft (Petersen et al., 2010;Kitano et al., 2021;Higashi et al., 2022). However, several promising solutions have been developed in organ tissue engineering to attain improved endothelialization. ...
... Although Grillo et al. reported a mean resectable tracheal length of 6.4 cm (4), this study was performed using formalin-fixed cadaver specimens, which deviate from normal physiological conditions in unique procedures, such as the division of the left main bronchus with reimplantation into the right bronchus intermedius. Similarly, Madariaga et al. analyzed 545 patients who underwent TRR and reported that the mean resected tracheal length was 3.5 cm (range, 1-6.3 cm) with tracheal release maneuvers, and 3.0 cm (range, 0.8-6.5 cm) without tracheal release maneuvers (21). Interestingly, the patient who underwent only 1 cm of tracheal resection in the study required the tracheal release maneuver, whereas the patient with 6.5 cm of tracheal resection did not undergo the tracheal release maneuver. ...
... The immunolabeled cells are vaporized in a nebulizer, and the number of heavy metal isotopes is reported through the mass channel as the antigen molecule expression level. As virtually no signal overlap is observed between different heavy metal isotopes, more than 40 cell parameters can be measured simultaneously in a single cell [33,34]. Based on the same principle, antibodies labeled with unique metal isotopes have also been used for immunostaining of formalin-fixed paraffin-embedded tissue sections, while multiplexed ion beam imaging technology has been used to obtain the imaging data, which could simultaneously detect more than 40 markers at subcellular resolution [35]. ...