Introduction

The trachea, or windpipe, is a crucial structure that enables airflow from the environment into our lungs. Damage or diseases affecting the trachea can result in life-threatening complications, often resulting in the need for surgical interventions like artificial trachea implantation when no other treatments are available. Following Dr. Paolo Macchiarini’s fake tracheal impacts,¹ this article will dive into the real medical advances for tracheal treatments that could help save so many lives. This article examines the latest developments in tracheal transplants and artificial tracheas, their clinical applications, and the future of these life-saving procedures.

Who could need a tracheal transplant?

Many conditions could give rise to the need for a new trachea, especially due to the vital function the trachea performs in the body. Conditions which could necessitate this include:²

1. Injury – Severe accidents, blunt trauma, or penetrating injuries that cause extensive tracheal damage, leading to airway obstruction
2. Birth Conditions – Certain congenital abnormalities, such as tracheomalacia (overly weak trachea that collapses during breathing) or congenital tracheal stenosis, can make normal breathing difficult and necessitate intervention. Although CPAP (continuous positive airway pressure) can work well to ameliorate the conditions initially, failure to improve can require surgical intervention, especially with stenosis greater than 2cm in length in children³
3. Tracheal Stenosis – This narrowing of the trachea, often caused by prolonged intubation, infections, or autoimmune diseases, can significantly restrict airflow. This is especially important with stenosis greater than 4-5cm long in adults³
4. Tumours/ Cancer – Both benign and malignant tumours can obstruct the airway, requiring surgical removal and reconstruction. These can originate from the trachea or from nearby structures that eventually affect the trachea
5. Affected surrounding structures – When other structures in the body are diseased, this can have downstream consequences on the trachea, such as subglottic stenosis (narrowing of the subglottis, below the vocal cords and above trachea)

The function of grafts and scaffolding in tracheal conditions

By offering structural support and encouraging tissue regeneration, scaffolding and grafts are essential in treating tracheal disorders.² To maintain the correct shape and functionality of the airway during healing, scaffolds—which are frequently composed of biodegradable materials—act as temporary frameworks that direct the development of new tracheal cells and tissues. Rebuilding functional tissue requires cellular attachment, proliferation, and differentiation, all of which they promote. Both synthetic and biological grafts aid in replacing injured tracheal segments, re-establishing the integrity and patency (flexibility and functionality) of the airway. These technologies can greatly increase the body's natural healing processes, lower the chance of rejection, and improve long-term outcomes for patients with complex tracheal abnormalities when paired with stem cells or bioactive compounds.

Now, let’s take a closer look at the different types of substances that can be used for tracheal grafting.

Polymers

Many polymers can now be 3D printed, which increases the variety of polymers that can be used for tracheal scaffolds and grafts. Of those extensively researched, many have properties that make them viable, including:²

• Polycaprolactone (PCL)
• Poly-lactic acid (PLA)
• poly-lactic-co-glycolic acid (PLGA)
• thermoplastic polyurethane skeleton

PCL has demonstrated excellent properties that make it ideal for use in tracheal grafting, including easily integrating with the existing trachea, producing a minimal immune response, and being able to replicate healthy tracheal functions within the body.^4,5

Animal studies have shown that it works well, even when it is spun into a mesh around solid rings of its own material, and can allow natural cilia to begin growth over its surface. Its degradation also hasn’t caused toxicity, with full integration into the native tracheal wall seen.^4,5 Forms of PCL have also given way to new blood vessels beginning to form to supply the tracheal graft to keep the cilia alive, with successful stents and splints placed in patients.^4,5,6

Instead of stimulating a low immune response, one researcher was able to use PLA fibres to create a patch that surrounded a thermoplastic polyurethane scaffold, and then graphene oxide treated with ionic liquid improved this by giving it antibacterial properties.^7,8 Studies with the body (in vivo) illustrated no infection or inflammation between the graft and the natural tissue, along with tissue regeneration. Additionally, the tissue responded with osmotic properties like natural tissue. Indeed, paediatric clinical trials using PLA stents and splints also showed that this was a viable material for tracheal surgery. 

PGA has a much faster degradation time of less than a year, although its other properties stimulate new cartilage formation to strengthen the existing weaker cartilage in animal studies. Although it offers similar benefits to PLA, such as non-toxicity, formation of new blood vessels and integration into the natural trachea, it has been shown to stimulate an inflammatory response by the immune system, thus leading to some scarring.⁸ This may be responsible for the greater rigidity seen, but the structure of the polymer itself may be responsible for being less flexible upon inhalation and exhalation than a natural trachea.^8,10 There was 100% survivability seen in the animal studies, though it may be possible that the size of the animal and the length of time they were observed contributed to this, as year down the line this may not be viable in human subjects. 

PLGA was also tested and had some favourable features such as flexible maintenance of the natural trachea. However, with a degradation time of 1-2 years, low levels of toxicity were observed if it took less than 2 full years to break down and an immune response was also seen.^9,11 This was the result of a peadiatric clinical trial, with all patients surviving the surgery. Future research on this may be focussed on decreasing natural degradation within the body, although the paediatric nature of the patients may use the PLGA microplate as a scaffold during early years after which it could possible no longer be required as the body corrects course and the trachea now can grow correctly on its own, dependant on the reason for the surgical intervention. 

In cases where this corrective course isn’t triggered, lifelong support in the form of non-degradable scaffolds may be required. Polypropylene and nickel-titanium alloys have been studied.⁹ Polypropylene was used for anastomotic surgery, with all animals surviving. Although there were low levels of stenosis seen, it wasn’t toxic, nor did it trigger an immune response.¹² However, in the case of nickel-titanium alloys for tracheal reconstruction, one of the animals in the study passed away within days of the surgery.¹³ The only human paediatric patient using a nickel-titanium alloy mesh for tracheal reconstruction survived.^11,13

Seeding grafts for better tissue regeneration

Seeding tracheal scaffolds and grafts with stem cells have demonstrated increased tissue regeneration for repair. Shin et al.(2014) explored the use of porcine (pig) cartilage powder combined with mesenchymal stem cells (MSCs) for tracheal defect repair in rabbits.¹⁴ Remarkably, none of the subjects experienced postoperative respiratory distress. Endoscopic evaluations revealed successful tracheal regeneration, showing healthy epithelium in the trachea without signs of collapse or blockage. After 10 weeks, the ciliary beating frequency of the regenerated tissue matched that of normal epithelium, indicating returning function.¹⁴

Similar outcomes were observed when porcine cartilage was seeded with chondrocytes, underscoring the effectiveness of scaffold-seed composites.¹⁵ Additionally, the integration of induced pluripotent stem cells (iPs) has opened new avenues for tracheal regeneration. Studies using iPs-derived silk fibroin collagen vitrigel membrane patches demonstrated the maintenance of mucosal epithelium and normal tracheal cellular function.¹⁶ In rat models, motile cilia were detected just two weeks after introducing iPs-based collagen scaffolds as tracheal segments.¹⁷

Kim et al. (2020) further advanced this research by developing tracheal grafts seeded with a combination of iPs-derived MSCs and chondrocytes.¹⁸ These engineered tracheas, implanted in rabbits with segmental defects, showed significant cartilage formation and mucociliary regeneration within four weeks. This multi-seed approach offers promising potential for future tracheal transplant innovations, emphasising the critical role of diverse cell types in achieving successful tissue regeneration.

Future research

Enhancing long-term functionality: artificial tracheas must replicate the biomechanical properties of native tracheas for optimal performance. Future research could shed more light on certain issues, including the use of these in human subjects. The majority of the research currently explored focused on tissue and animal usage, and although the effects could mimic human use, it is possible that in vivo effects may differ for both physiological and anatomical differences. Trying this in larger animals that have tracheas that are similar in size to humans could also aid in evaluating the true efficacy of these, especially in the case of de novo tracheas for transplantation. Other materials beneficial for the use of long-term, non-degradable tracheas may also be researched to provide optimal support, integration and functionality without rejection or inflammation. 

Some animals also showed that the inserted graft or scaffold migrated within the trachea, resulting in a secondary operation to remove it. Greater research into perhaps preventing migration or anchoring of the scaffolds in humans could also be explored. 

Summary 

Several advances have been made for surgical intervention in tracheal anomalies, with PCL offering the best properties for reconstruction, especially when enhanced with ionic liquid graphene oxide for antibacterial properties. There are a number of ways to grow stem cells on these scaffolds for regenerative properties, with success in many cases. However, more research is required when transplanting these substances into larger animals like humans who have differing anatomy to the smaller animals which have currently been relied upon for the majority of in vivo tests. There have been some successful surgical implants in humans which demonstrate that this is viable, though ways to minimise rejection and inflammatory responses/ scarring are required to make this a viable intervention to add to a list of viable treatments.