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Tissue Engineering Approaches to Treat COPD

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ClinicalTrials.gov Identifier: NCT04878445
Recruitment Status : Recruiting
First Posted : May 7, 2021
Last Update Posted : May 7, 2021
Sponsor:
Information provided by (Responsible Party):
University Hospitals of North Midlands NHS Trust

Study Description
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Top of Page Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information
Brief Summary:

The study is a pilot/laboratory study comparing lung tissue from control participants with tissue from COPD participants with a chronic bronchitis or emphysema phenotypes. Tissue will be characterised mechanically and biochemically.

Lung cells, including DASCp63/Krt5 with a possible role in disease pathology, will be isolated, expanded in vitro, characterised, and banked. Biomaterials will be selected and tested with regards to mechanical and physical properties and selected for use in the production of TELEs with properties matched to healthy and diseased lung tissue.

The resulting TELEs will be tested in an ex vivo tissue culture model to determine the extent of their integration with lung.


Condition or disease Intervention/treatment
Lung Cancer Procedure: Patients undergoing standard surgery, excess tissue only will be analysed with patient consent.

Detailed Description:

Chronic obstructive pulmonary disease (COPD) is currently ranked as the third leading cause of death with an annual associated global healthcare cost of £1.3 trillion (1). It is the second most common cause of emergency hospital admissions with high morbidity and mortality. COPD results in a progressive loss of lung function, leading to respiratory failure. This loss of lung function is associated with repetitive cycles of inflammation and parenchymal scarring leading to the development of emphysema. This is a consequence of the breakdown of the delicate parenchymal structures and lung remodelling, with accumulation of fibrous tissue and loss of the alveolar-capillary functional units that are essential for effective gas exchange. Macroscopically the lungs become stiffer and unable to support the patient through the physiological inhalation/exhalation breathing cycles (2).

The presence of emphysema also results in the loss of lung elastic recoil as pockets of air form in place of damaged bronchioles and alveoli reducing the available volume for the next inhalation. The collapse of the airways during exhalation leads to increased lung volumes causing hyperinflation and gas trapping. Patients become progressively symptomatic with increasing breathlessness, reduced exercise tolerance and poor quality of life.

The pharmacological treatment options for emphysema are limited; current therapy aims to improve airflow limitation, reduce airway inflammation and reduce exacerbations, but does not reverse lung damage (3). Lung transplantation and lung volume reduction surgery (LVRS) is available for a selected minority of patients with severe emphysema. The recent introduction of non-invasive endoscopic mechanical treatment with Valves reduces severely damaged lung volume and re-directs air to the healthier tissue while Coils improves elastic lung recoil (4, 5). These interventions however do not improve survival.

Previous work performed within our laboratories has determined that hydrogel/elastin-based constructs can achieve mechanical values consistent with those of the alveolar wall when seeded with lung fibroblasts (1). This raises the intriguing question of whether tissue-engineered constructs (TEC) could be used to restore mechanical integrity of the emphysematous lung, via air pocket displacement and local integration, and ultimately by regeneration of local lung architecture.

Coupled to the work described above a recent observation went some way to detailing the mechanism behind the previously misunderstood, but physiologically critical, capacity for lung tissue to regenerate following on from acute disease such as pneumonia or acute respiratory distress syndrome (6). The key appears to lie with a population of distal airway stem cells who co-express Trp63 (p63) and Keratin 5 (Krt5). These DASCp63/Krt5 cells appear to migrate to sites of injury in the lung where they have demonstrated differentiation capacity including lineages such as type I and II pneumocytes and bronchiolar secretory cells. It is crucial to our understanding of chronic lung disorders, and design of future cell-based therapies, whether these cells remain present and dormant in diseased lung tissue or lost through as yet unknown mechanisms.

Study Design
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Study Type : Observational
Estimated Enrollment : 30 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: A Tissue Engineering Approach to Improve Lung Function and Clinical Outcome in Patients With COPD
Actual Study Start Date : August 31, 2017
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2023

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort Intervention/treatment
Cohort A: 10 participants with no COPD

Control patients Have no physician diagnosis of COPD Have no other significant chronic lung disease (asthma, fibrotic diseases) or ongoing lung infection other than the suspected cancer for which they have been referred for surgery.

Lifelong never-smokers or ex-smokers (< 10 pack years). (1 pack year= 20 cigarettes/day for 1 year).

 Procedure: Patients undergoing standard surgery, excess tissue only will be analysed with patient consent.
Lung samples will be obtained from surplus, healthy margin lung tissue resected from patients with suspected or confirmed lung cancer or from resected tissue from lung volume reduction surgery.
Cohort B: 10 participants with COPD - chronic bronchitis
Have a physician diagnosis of COPD with primarily a chronic bronchitis presentation (determined via CT, spirometry, histopathology, GOLD COPD classification).
 Procedure: Patients undergoing standard surgery, excess tissue only will be analysed with patient consent.
Lung samples will be obtained from surplus, healthy margin lung tissue resected from patients with suspected or confirmed lung cancer or from resected tissue from lung volume reduction surgery.
Cohort C: 10 participants with COPD emphysema
Have a physician diagnosis of COPD with primarily a emphysema presentation (determined via CT, spirometry, histopathology, GOLD COPD classification) .
 Procedure: Patients undergoing standard surgery, excess tissue only will be analysed with patient consent.
Lung samples will be obtained from surplus, healthy margin lung tissue resected from patients with suspected or confirmed lung cancer or from resected tissue from lung volume reduction surgery.


Outcome Measures
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Primary Outcome Measures :
  1. The overall aim of this project is to produce in vitro tissue engineered lung equivalents (TELEs) seeded with cells obtained from: [ Time Frame: Through study completion upto 1 year ]

    P1) The determination of the scale-up suitability of in vitro lung equivalents, their mechanical properties, and in vitro degradation rates.

    P2) Development of in vitro DASCp63/Krt5 culture models to support re-establishment of local lung architecture.

    P3) Establishment of ex vivo lung culture models to support the lung tissue equivalents' evaluation.



Secondary Outcome Measures :
  1. To achieve an understanding of the mechanical properties of diseased and healthy lung tissue. [ Time Frame: Through study completion, upto 1 year ]

    To evaluate and tune hydrogel or foamed biomaterials to identify compositions which reflect the properties of healthy and diseased lung tissue.

    S3) Creation of lung cell banks e.g. fibroblasts, pneumocytes, club cells, from diseased and healthy tissue.

    S4). The identification of the presence/absence of DASCp63/Krt5 in healthy/diseased lung tissue and disease-association with retention of properties.

    S5). Insertion of tissue engineered lung pieces into ex vivo lung slice culture and evaluation of cell spreading and construct integration.



Biospecimen Retention:   Samples With DNA
Lung cells, including DASCp63/Krt5 with a possible role in disease pathology, will be isolated, expanded in vitro, characterised, and banked. Biomaterials will be selected and tested with regards to mechanical and physical properties and selected for use in the production of TELEs with properties matched to healthy and diseased lung tissue.

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Sampling Method:   Probability Sample
Study Population
Chronic obstructive pulmonary disease (COPD) is currently ranked as the third leading cause of death with an annual associated global healthcare cost of £1.3 trillion. It is the second most common cause of emergency hospital admissions with high morbidity and mortality. COPD results in a progressive loss of lung function, leading to respiratory failure. This loss of lung function is associated with repetitive cycles of inflammation and parenchymal scarring leading to the development of emphysema. This is a consequence of the breakdown of the delicate parenchymal structures and lung remodelling, with accumulation of fibrous tissue and loss of the alveolar-capillary functional units that are essential for effective gas exchange. Macroscopically the lungs become stiffer and unable to support the patient through the physiological inhalation/exhalation breathing cycles.
Criteria

Inclusion Criteria:

  • Men or women aged over 18 years- .
  • Must be competent to give written informed consent.
  • Scheduled to undergo clinical indicated surgery to remove lung tissue.

Exclusion Criteria:

  • Patient unable to give informed consent
  • Significant long term condition or lung pathology (infection, asthma, fibrotic lung diseases) other than that for which they have been referred for surgery.

Post Surgery

• Insufficient tissue removed to supply the laboratory study after consultation with the Consultant histopathologist.

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04878445


Contacts
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Contact: Robert Bowler 07592800964 ext 07592800964 robert.bowler@uhnm.nhs.uk
Contact: Mohammed Haris 01782 6 ext 75950 Mohammed.Haris@uhnm.nhs.uk

Locations
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United Kingdom
University Hospitals of North Midlands NHS Trust Recruiting
Stoke-on-Trent, Staffordshire, United Kingdom, ST4 6QG
Contact: Robert Bowler    017826 ext 71939    robert.bowler@uhnm.nhs.uk   
Contact: Keira Watts    017826 ext 75385    keira.watts@uhnm.nhs.uk   
Principal Investigator: Mohammed Haris         
Sponsors and Collaborators
University Hospitals of North Midlands NHS Trust
More Information
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Top of Page Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information
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Responsible Party: University Hospitals of North Midlands NHS Trust
ClinicalTrials.gov Identifier: NCT04878445    
Other Study ID Numbers: 1517
First Posted: May 7, 2021    Key Record Dates
Last Update Posted: May 7, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No