Lung tissue bioengineering for chronic obstructive pulmonary disease: overcoming the need for lung transplantation from human donors

ABSTRACT

Introduction: Chronic obstructive pulmonary disease (COPD) affects more than 380 million people, causing more than 3 million deaths annually worldwide. Despite this enormous burden, currently available therapies are largely limited to symptom control. Lung transplant is considered for end-stage disease but is severely limited by the availability of human organs. Furthermore, the pre-transplant course is a complex orchestration of locating and harvesting suitable lungs, and the post-transplant course is complicated by rejection and infection. Lung tissue bioengineering has the potential to relieve the organ shortage and improve the post-transplant course by generating patient-specific lungs for transplant. Additionally, emerging progenitor cell therapies may facilitate in vivo regeneration of pulmonary tissue, obviating the need for transplant.

Areas Covered: We review several lung tissue bioengineering approaches including the recellularization of decellularized scaffolds, 3D bioprinting, genetically-engineered xenotransplantation, blastocyst complementation, and direct therapy with progenitor cells. Articles were identified by searching relevant terms (see Key Words) in the PubMed database and selected for inclusion based on novelty and uniqueness of their approach.

Expert Opinion: Lung tissue bioengineering research is in the early stages. Of the methods reviewed, only direct cell therapy has been investigated in humans. We anticipate a minimum of 5–10 years before human therapy will be feasible.

KEYWORDS:

• COPD
• lung bioengineering
• cell therapy

Article Highlights

• COPD affects over 380 million people and causes over 3 million deaths annually worldwide with an annual financial burden of $18 billion in the USA and $$47.3 in the EU.

• Current therapies are palliative; there is no cure for COPD. Lung transplant is an option in end-stage disease but is limited by the dearth of available human donors.

• Low-risk immune matching is not possible in lung transplant and the post-transplant course is complicated by infections, side effects from anti-rejection medications, and chronic low-level rejection. The 5-year survival is only 55% and survival decreases to 32% at 10 years.

• Bioengineering techniques are being investigated to generate patient specific transplantable lungs to overcome the need for human donors and reduce the risk of rejection.

• Xenotransplantation with genetically modified animal organs is in its early phase and still fraught with overwhelming rejection.

• Recellularization of decellularized lung scaffolds, possibly with patient-sourced, iPSC-derived cells, is another proposed technique. Recellularized scaffolds are capable of gas exchange for hours to days in animal transplant studies, though vascular occlusion or leak lead to eventual failure.

• 3D bioprinting has been used to produce biologic constructs including trachea. Current printers and bioinks are not capable of the required resolution for pulmonary tissue, but the field is advancing rapidly.

• Blastocyst complementation is investigated as a strategy to grow human organs in animals by deleting organ-specific host genes; however, additional gene targets need to be identified before lung generation will be possible.

• Direct therapy with mesenchymal stromal cells in humans has been investigated in small phase I and II trials. The therapy appears safe, and although no significant benefit has been found, a trend towards improvement was identified by some studies. Larger studies are needed.

• Despite the many avenues of research, none of these techniques are currently ready for general clinical application. We anticipate it will be at least 10 years before bioengineered lung tissues are available to patients.

• This box summarizes key points contained in the article

Declarations

Steven Skolasinski has received support from NIH/NHLBI F32HL141056. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers Disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Declaration of interest

No potential conflict of interest was reported by the authors.