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Dinaki et al. | Journal of Clinical and Translational Research 2024; 10(2): 99-111 105
trial reported that all patients displayed improvements in speech The human larynx is typically decellularized to effectively
function and acoustic and aerodynamic measurements. produce scaffolds. Baigueraet al. evaluated the effectiveness of the
Hepatocyte growth factor (HGF) is another growth factor that modified detergent-enzyme method (DEM) as a decellularization
regulates cell proliferation and differentiation and is commonly technique for creating human laryngeal acellular matrices that
associated with vocal fold recovery. HGF has an antifibrotic effect are structurally and mechanically comparable to the original
and can boost HA levels, reduce collagen production, and stimulate larynx [87]. Twenty-five cycles of DEM created a bioengineered
cell growth and migration [75]. In the event of an injury to the human laryngeal matrix that was physically and mechanically
vocal folds, HGF can be found in the LP and the epithelium, and identical to the biological larynx with pro-angiogenic factors.
its angiogenic and antifibrotic properties could facilitate wound Al-Qurayshi et al. evaluated the effect of DEM on the larynx and
healing of the vocal folds [76]. In one study, it was reported that cricoarytenoid joint of human cadavers. In this study, five fresh
HGF prevented excessive collagen deposition and restored the frozen human cadaveric larynxes were effectively decellularized,
levels of elastin, collagen, or HA to normal levels relative to an as evidenced by the considerable DNA depletion and ECM
uninjured vocal fold [77]. Hirano et al. also conducted a clinical preservation, to regenerate a non-immunogenic larynx from a
trial involving 18 individuals with vocal fold scarring or sulcus, biological scaffold [88]. However, the use of numerous detergents
and the findings of the trial indicated an improvement in voice and enzymes in DEM weakened the cricoarytenoid joints. Moser
measurements [78]. et al. recently described the synthesis of laryngeal grafts utilizing
decellularized canine laryngeal scaffolds that were recellularized
5.4. Vocal fold scaffolds
with primary human cells, and this provided the foundation for
Several types of scaffolds have been developed for 3D LP developing functional laryngeal scaffolds with composite tissue
replacement, including biological polymers, decellularized grafts [89]. In another study, Huber et al. used a porcine-derived
organ matrices, synthetic biomimetic hydrogels, and synthetic ECM to reconstruct the larynx in mature dogs, demonstrating
polymers [79]. These scaffolds can be either injected or attached the constructive remodeling of a xenogeneic acellular biological
during surgery, wherein the scaffolds have biomechanical scaffold material [90]. Thyroid cartilage and thyroarytenoid
similarities with the LP, transport cells, and other bioactive muscle were restored, and histologic investigation revealed
components. Imaizumi et al. successfully employed biodegradable glandular structures, a complete epithelial lining, cartilaginous
gelatin hydrogel microspheres as a delivery vehicle for bFGF in a structures, and skeletal muscle tissue in the reconstructed tissue.
rabbit model with vocal fold damage, and the larynxes reportedly The microstructure and macrostructure of the recreated tissue were
displayed better vibratory function and reduced scarring based on nearly the same as the original. Porcine laryngeal scaffolds were
histological assessments [80]. HA-modified hydrogel scaffolds decellularized and subsequently seeded with human BM-MSCs
have reportedly promoted fibroblast spreading, proliferation, and in two recent studies on laryngeal replacement [91,92]. Both of
collagen/glycosaminoglycan production [81]. Likewise, acellular the studies featured the decellularization of the whole larynx and
biological scaffolds have similar biological composition and the production of a safe and biocompatible biological scaffold
architecture as native tissues. Therefore, the biological scaffolds with the ability to stimulate re-epithelialization and submucosal
can facilitate host cell adhesion, motility, and infiltration and development. More importantly, the implanted scaffolds supported
secrete pro-angiogenic growth factors [82]. normal respiratory functions, in addition to proper swallowing
and vocalization. The aforementioned studies and their promising
5.5. Larynx results have established the prospect of successful functional partial
The larynx is composed of multiple tissue types, which presents laryngectomy reconstruction and total laryngeal regeneration.
as a challenge when restoring its function and structure. Patients 5.6. Trachea
with an advanced primary tumor have limited treatment options.
Total or partial laryngectomy (removal of part or all of the larynx) Patients with congenital malformations or acquired
remains the primary treatment method for advanced primary tracheal stenosis after trauma or malignancy are candidates for
tumor, but this would lead to speech, breathing, and swallowing reconstruction as other minor defects can be easily managed
deficiencies. Nonetheless, bioengineered laryngeal structures with tracheal resection and end-to-end anastomosis. Airway
have been developed and tested in animal and human models. reconstruction requires a combination of scaffolds seeded
Animal studies have demonstrated that cartilage-like grafts may with cells. In particular, two studies involving children utilized
be effectively employed for partial laryngeal cartilage replacement decellularized deceased donor trachea [2,93,94]. In the first
when stem cells are grown in the scaffolds [48,83]. In contrast, study, the decellularized cadaveric donor tracheal scaffolds
aortic allografts have been utilized to repair hemilaryngeal were planted with BM-MSCs and autologous epithelium before
abnormalities in human studies [84,85]. Brookes et al. conducted transplantation in a 12-year-old child suffering from congenital
the first animal study demonstrating that primary skeletal muscle stenosis of the trachea. The child was topically applied with
progenitor cells and standardized oligomeric collagen may be human recombinant erythropoietin to stimulate angiogenesis
used to generate functioning, 3D tissue-engineered skeletal and transforming growth factor to promote chondrogenesis. At
muscle [86]. the 2-year follow-up, the child had a functioning airway and had
DOI: https://doi.org/10.36922/jctr.22.00151