Page 336 - Read Online

Velasquillo et al. Plast Aesthet Res 2020;7:31 I http://dx.doi.org/10.20517/2347-9264.2020.30 Page 7 of 14

auricle shaped mold. Research started focusing on scaffolds that could promote cell proliferation, as well as
matrix production. Decades later, research focused on finding the ideal scaffold that would induce cellular
[79]
[80]
proliferation and cartilage tissue formation. This was proved by Vacanti et al. and Rodriguez et al. ,
who conducted several preclinical studies showing that polyglycolic acid (PGA) + polylactic acid (PLA)
would promote in vitro cell proliferation and matrix production, and in vivo cartilage formation after
implantation. Mice were implanted with 3D ear-shaped scaffolds seeded with chondrocytes. After 12 weeks,
scaffolds were almost entirely degraded; however, the neo-tissue maintained the original 3D structure and
demonstrated histological cartilage appearance. These studies were the introduction of biotechnology to
[81]
regenerative medicine .

The combination of seeded auricular chondrocytes (AuCs) to scaffolds and the computer-assisted design/
computer-aided manufacturing (CAD/CAM) technology [82-84] led to the start of clinical studies. The
[84]
first clinical application was done in Shanghai in 2018 by Guangdong Zhou et al. , where 5 patients
with unilateral microtia were implanted with 3D printed PCL + PGA scaffolds seeded with autologous
chondrocytes from the cartilage remnants of the microtia. 2.5 years later, they reported the follow-up of one
patient showing the formation of cartilaginous tissue after histologic evaluation, the transition from a stiff
graft to a more flexible one over the time, and the degradation of the scaffold without losing the original ear
shape.

Currently, autologous chondrocytes from the microtia auricle are being isolated, expanded, and seeded
[85]
onto the constructs, showing normal elastic cartilage on histology . However, monolayer expansion
of chondrocytes results in dedifferentiation [80,86] , limiting the capacity to generate robust cartilage,
and needs extensive 3D construct culture before implantation [84,87] . Mesenchymal stem cells have the
potential of massive expansion and the ability to differentiate into chondrocytes through co-culture or co-
[88]
implantation .
Studies have been done using articular cartilage co-cultures with MSC, though little is known about AuCs
and MSC. Pre-clinical in vivo studies have shown the formation of cartilage, but the impact of these studies
is limited due to the use of non-human cells, the lack of specific markers for elastic cartilage, and the
[95]
absence of mechanical evaluation [89-94] . Cohen et al. conducted a comparative preclinical study evaluating
cartilage formation in constructs using human AuCs vs human AuCs and MSC in a 1:1 ratio. The study
showed that the auricular cartilage generated in the 1:1 constructs was similar in structure, histology,
biochemical development, and mechanical properties to discs containing only AuCs and native human
auricular cartilage after 3 months in vivo. To date, no clinical study using AuCs in combination with MSC
has been conducted. However, these findings suggest MCSs could solve several problems related to cartilage
culture and could bring other benefits related to their immunomodulatory/anti-inflammatory potential.

Cleft lip and palate
Cleft lip (CL) and palate (CLP) are common congenital malformations in Mexico, with an incidence of 1 in
[96]
800 births . Up to 2003, CLP had a prevalence of 139,000 affected children throughout the country, with
[97]
approximately 10 new cases identified daily .

Patients with CLP undergo (on average) 4 surgical procedures during their lifetime: (1) lip closure and
[98]
primary nasal repair; (2) palate closure; (3) alveolar bone graft; and (4) rhinoseptoplasty . The alveolar
bone graft is the placing of bone in the primary palate to restore the continuity of the maxillary arch and
separate the oral and nasal cavity [99,100] . This allows adequate dental hygiene, promotes harmonic facial
growth, and provides the necessary bone matrix for the eruption of the lateral and canine incisors [101,102] .

3
The best donor area for the bone graft is the iliac crest, where approximately 3-8 cm of bone are obtained.
Several problems are associated with this procedure, such as recipient area alterations (lack of integration,