This is a prospective, open-label, multi-center, single-arm study to be conducted at up to 20 investigational sites. The Study plans to enroll up to 140 subjects with severe emphysema and collateral ventilation in the target lobe. This protocol is designed to evaluate the utility of the AeriSeal System to occlude collateral air channels in a target lung lobe with collateral ventilation (CV) and convert the target lung lobe to having little to no collateral ventilation. Subjects can then receive Zephyr Valves to achieve atelectasis in the targeted lobe, once AeriSeal has converted the CV+ lobe to a CV- one. Therefore, the study will have two Stages:

• Stage 1 will address the closure of the lobar fissure gaps (or collateral air channels) to block collateral ventilation (CV) with the AeriSeal System; conversion of the CV+ target lobe to CV-. Conversion of collateral ventilation will be evaluated by Chartis after 45 days. In the case of unsuccessful conversion, a second treatment of AeriSeal may be attempted, provided that the total application volume from both the initial and the repeat treatments does not exceed 40 mL in up to three (3) segments.

Clinical Assessments post-AeriSeal will be conducted at 28 and 45 days after first treatment and repeated after the second treatment, if applicable. For the purpose of protocol follow-up, the Day 45 post-AeriSeal final treatment will equal Day 0 for Stage 2.

• Stage 2 will include successfully converted subjects; CV+ to CV- conversion in Stage 1. Converted CV- target lobes will follow standard of care and receive CE marked Zephyr Endobronchial valves per the Zephyr IFU to perform bronchoscopic lung volume reduction (BLVR).

Clinical assessments will be conducted at 45 Days, 3-months, 6-months, and 12-months post-Zephyr Valve procedure.

Severe emphysema subjects will be consented using an Ethics Committee approved Informed Consent Form (ICF) for baseline evaluations. Subjects with ≥ 50% lobar emphysema destruction (evaluated quantitatively by using percentage lung volume occupied by low-attenuation regions/voxels) and identified as potentially having collateral ventilation, with fissure completeness ≥ 80% from the Quantitative Computed Tomography (QCT) report (CV status later to be confirmed by Chartis assessment at Visit 2) will undergo additional QCT assessment for the feasibility of directing AeriSeal to the appropriate segment to seal the anatomical defect. Subjects in whom this is considered feasible will be enrolled.

Enrolled subjects will undergo a bronchoscopy procedure during which the presence of collateral ventilation will be confirmed using the Chartis Pulmonary Assessment System (Pulmonx Corporation) and if confirmed, will undergo AeriSeal treatment in the segment(s) feeding the collateral channel. A minimum 10 mL volume of AeriSeal will be delivered per segment, with a total delivered volume limit of 40 mL per subject (including re-treatment, if needed) in a total of three segments. Subjects will be hospitalized for a minimum of two (2) nights for observation and discharged if stable. Following discharge, subjects will be contacted daily for at least 7 days via telephone to assess status and solicit any Adverse Events.

Subjects that have little to no collateral ventilation at the initial bronchoscopy, as assessed by the Chartis Pulmonary Assessment System, will be exited from the study.

Six (6) weeks following the AeriSeal treatment, subjects will undergo a second bronchoscopy procedure for assessment of collateral ventilation status of the AeriSeal treated lobe with Chartis. If the Chartis assessment shows presence of collateral ventilation (CV+) at the lobar level, Chartis will be used to assess collateral ventilation at the segmental level to identify the segment with open collaterals. A second treatment with AeriSeal will be considered, provided the total delivered volume inclusive of the original treatment does not exceed 40 mL per subject. The post-procedure follow-up assessments for the second treatment will be repeated as after the initial treatment.

If the Chartis assessment determines little to no collateral ventilation (CV-) in the AeriSeal treated lobe, the lobe will be treated with Zephyr Valves as per the standard valve placement procedure. Subject will be hospitalized for a minimum of three (3) nights post-valve placement procedure and discharged with follow-up in accordance with this protocol, which includes standard post-valve placement follow-up.

Subjects who do not convert from CV+ to CV- status will continue to be observed for safety through 12 months following AeriSeal treatment or re-treatment, whichever is later.

The primary AeriSeal endpoint is the percentage of study subjects that are successfully converted from a positive collateral ventilation (CV+) status in the treated lobe to having little to no collateral ventilation (CV-) in the treated lobe.

Following the procedure for Zephyr Valve placement, subjects will be required to undergo Pulmonary Rehabilitation as per the local/national guidelines of each participating institution; at least 20 supervised sessions. A High Resolution Computed Tomography (HRCT) will be performed at 45-days post-Zephyr Valve procedure to determine Treated Lobe Volume Reduction (TLVR). Lung function will be assessed by measuring post-bronchodilator FEV1. A valve adjustment procedure will be considered if there is lack of TLVR (≤ 350 mL reduction from the pre-valve assessment) following evaluation of the High-resolution computed tomography (HRCT) to determine which valve needs to be replaced or addition of a new valve at a previously missed airway. Subjects will also be evaluated at 3-months, 6-months, and 12 months following Zephyr Valve placement.

Inclusion Criteria:

1. Subject is willing and able to provide Informed Consent and to participate in the study.
2. Subject is ≥ 40 and ≤ 75 years of age at the time Informed Consent signature.
3. Subject has at least one lobe with ≥ 50% emphysema destruction (at -910 HU) as determined by QCT.
4. Subject has a diagnosis of homogenous or heterogeneous emphysema, confirmed by HRCT scan. Heterogeneous emphysema defined as ≥ 15% difference (at -910 HU) in emphysema destruction score of adjacent lobes by HRCT.
5. Subject has a gap in the interlobar fissure that corresponds to one or more segments as determined by QCT.
6. Subject has clinically significant dyspnea with a mMRC Dyspnea score ≥ 2.
7. Subject has a Six-Minute Walk Distance ≥ 250 meters.
8. Subject has post-bronchodilator FEV1 ≥ 15% predicted and ≤ 50% predicted.
9. Subject has post-bronchodilator Total Lung Capacity ≥ 100% predicted.
10. Subject has post-bronchodilator Residual Volume ≥ 150% predicted if heterogeneous emphysema and ≥ 200% predicted if homogeneous emphysema.
11. Subject has stopped smoking for at least eight (8) weeks prior to Screening visit as confirmed by carboxyhemoglobin or cotinine levels.
12. Subject has received preventive vaccinations against potential respiratory infections consistent with local recommendations or policy.

Exclusion Criteria:

1. Subject has severe bullous emphysema where bulla is ≥ 1/3 of the total lung volume.

2. Subject has had prior lung volume reduction surgery, prior lobectomy or pneumonectomy, prior lung transplantation, prior airway stent placement, prior ipsilateral pleurodesis, or prior endobronchial lung volume reduction therapy of any type.

3. Subject has evidence of active respiratory infection.

4. Subject has an ongoing COPD exacerbation or bronchospasm.

5. Subject has a known allergy to the device components:

   1. Polyether block amide - PEBAX®
   2. Polyvinyl Alcohol
   3. Glutaraldehyde
   4. Nitinol (nickel-titanium) or its constituent metals (nickel or titanium)
   5. Silicone

6. Subject requires invasive ventilatory support (NOTE: The use of continuous Positive Airway Pressure (CPAP) and BiPAP devices for Sleep Apnea is permitted).

7. Subject has post-bronchodilator Diffusion Capacity (DLCO) < 20% predicted.

8. Subject cannot tolerate corticosteroids or relevant antibiotics.

9. Subject has other relevant comorbidities as judged by the Investigator or is deconditioned and cannot tolerate the stress of post-treatment inflammatory response.

10. Subject has had three (3) or more COPD exacerbations requiring hospitalization during the year prior to Informed Consent signature.

11. Subject has severe gas exchange abnormalities as defined by any one of the following (test conducted at rest on room air as tolerated, or on up to 4 L/min supplemental O2):

    1. PaCO2 ≥ 55 mm Hg (7.3 kPa)
    2. PaO2 < 45 mm Hg (6.0 kPa)
    3. SpO2 < 90%

12. Subject has uncontrolled pulmonary hypertension, defined as peak pulmonary systolic pressure > 45 mm Hg on echocardiogram or right heart catheterization.

13. Subject use of systemic steroids > 20 mg/day prednisolone or equivalent within 4 weeks of Informed Consent signature.

14. Subject use of immunosuppressive agents within four (4) weeks of Informed Consent signature.

15. Subject whose use heparins and oral anticoagulants (e.g., warfarin, dicumarol) cannot be discontinued according to local pre-procedural protocols. Note: antiplatelet drugs including aspirin and clopidogrel are permitted.

16. Subject's CT scan indicates the presence of any the following radiologic abnormalities:

    1. Pulmonary nodule on CT scan greater than 0.8 cm in diameter (Does not apply if present for one (1) year or more without increase in size or if proven benign by biopsy).
    2. Radiologic picture consistent with active pulmonary infection, e.g., unexplained parenchymal infiltrate.
    3. Significant interstitial lung disease.
    4. Significant pleural disease.

17. Subject's baseline EKG indicates non-atrial arrhythmias or conduction abnormalities.

18. Subject has high cardiac risk after undergoing cardiac risk assessment in accordance with published guidelines or ischemic heart disease, congestive heart failure, renal failure, or cerebrovascular disease.

19. Subject has clinically significant asthma (reversible airway obstruction), chronic bronchitis, or bronchiectasis.

20. Subject has allergy or sensitivity to medications required to safely perform bronchoscopy under conscious sedation or general anesthesia.

21. Subject participated in an investigational study of a drug, biologic, or device not currently approved for marketing within 30 days prior to Screening visit. Subjects being followed as part of a long-term surveillance of a non-pulmonary study that has reached its primary endpoint are eligible for participation in this study.

22. Subject has Body Mass Index (BMI) < 18 kg/m2 or > 35 kg/m2.

23. Subject is a female who is pregnant, breast-feeding, or planning to be pregnant in next 12 months.

24. Subject has clinically significant abnormal screening laboratory test results per the Institution specific reference laboratory normal values for the following:

    1. White blood cells (total)
    2. Hematocrit
    3. Platelets
    4. Prothrombin time or INR
    5. Partial thromboplastin time
    6. Positive β-HCG Pregnancy test (if female)

25. Subject has evidence of severe disease which in the judgment of the Investigator may compromise survival for the duration of the study (at least 12 months) e.g.:

    1. HIV/AIDs
    2. Active malignancy
    3. Stroke or Transient Ischemic attack (TIA) within 12 months of Screening visit
    4. Myocardial infarction within six (6) months of the Screening visit
    5. Congestive heart failure within six (6) months of the Screening visit defined as clinical evidence of right or left heart failure or left ventricular ejection fraction < 45% on echocardiogram

26. Subject has uncontrolled diabetes mellitus.

27. Subject has any other condition that the Investigator believes would interfere with the intent of the study or would make participation not in the best interest of the subject including but not limited to alcoholism, high risk for drug abuse, or noncompliance in returning for follow-up visits.