Biomaterials for Cleft Lip and Palate Regeneration

Abstract

Craniofacial bone defect anomalies affect both soft and hard tissues and can be caused by trauma, bone recessions from tumors and cysts, or even from congenital disorders. On this note, cleft/lip palate is the most prevalent congenital craniofacial defect caused by disturbed embryonic development of soft and hard tissues around the oral cavity and face area, resulting in most cases, of severe limitations with chewing, swallowing, and talking as well as problems of insufficient space for teeth, proper breathing, and self-esteem problems as a consequence of facial appearance. Spectacular advances in regenerative medicine have arrived, giving new hope to patients that can benefit from new tissue engineering therapies based on the supportive action of 3D biomaterials together with the synergic action of osteo-inductive molecules and recruited stem cells that can be driven to the process of bone regeneration. However, few studies have focused on the application of tissue engineering to the regeneration of the cleft/lip and only a few have reported significant advances to offer real clinical solutions. This review provides an updated and deep analysis of the studies that have reported on the use of advanced biomaterials and cell therapies for the regeneration of cleft lip and palate regeneration.

Keywords: bone; cleft lip; cleft palate; craniofacial defects; musculoskeletal tissue engineering; orofacial disorders; regenerative medicine.

Figure 1

Human stem cells, biomimetic scaffolds, and regenerative molecule signals as fundamental pieces of the tissue engineering puzzle for cleft/lip palate regeneration.

Figure 2

World incidence of cleft lip/palate per surgeon, anthologist, and obstetrician (SAO) in each country. Reproduced from Massenburg et al. (2018) [11] with permission from Springer ©.

Figure 3

Image of a patient with unilateral cleft palate showing the different tissues involved (bone, dental organs, respiratory system and soft tissue) that need to be attended during the treatment and some malformation around the orofacial area responsible for causing respiratory and speech/language problems. Deformation of the arch and dental crowding (A), crossbite dental malposition (B), and the deviated nasal septum (C) as revealed by panoramic radiographs showing the maxillary defect (circle) (unpublished data).

Figure 4

(Left) Scanning electron microscope views of the HA/TCP scaffolds Ceraform^® seeded with Adipocyte stem cells (ADSCs) used for human maxillofacial reconstruction showing the ability of ADSC to adhere on the surface of and colonize the inner pores of the scaffolds. (Right) Alkaline phosphatase analysis of osteogenically differentiated BMSC cells after three days of cultivation on bovine hydroxyl apatite/collagen scaffolds. Reproduced from Pourebrahim et al. (2013) [10] and Korn et al. (2017) [24] with permission from Elsevier and Springer^®, respectively.

Figure 5

(Left) Induced bone formation by beta-TCP in the maxillary cleft of goats (A). Material (stars) is reabsorbed by a multinucleated osteoclast-like cell (arrowhead) (B). Elsewhere, cuboidal osteoblasts (black arrow heads) lay down new bone (pink) adjacent to an osteocyte (white arrow) in its lacuna. Reproduced from Janssen et al. (2017) [22] with permission from SAGE Publications ^®. Scale bars: 250 μm (left), 25 μm (right A, B).

Figure 6

Human dental pulp stem cells seeded in multiwall carbon nanotubes with PCL at day 21 with potential application in CL/P regeneration. Osteopontin labeled antibody was used to evaluate the expression of bone phenotype markers, nuclei were counter stained with DAPI (unpublished data). Scale bars: 10 μm (left), 100 μm (right).

Figure 7

Analysis of a patient custom made patient cryogel. (a) SEM images taken at 1000 and 200X (left to right). (b) mCT 3D reconstruction images representing both the scaffold (grey) and the inner pores with the color bar denoting the size of the pores within the cryogel (left to right). Reproduced from Hixon et al. (2017) [45] with permission from SAGE^®.

Figure 8

Micro-computed tomography images of cranial defects treated with TCP/SrFO scaffolds at 4, 12, and 20 weeks, and defect closure on the side of the implants form the coronal plane (arrows) and 3D images (circles) and bone density of the radiographic density (HU) in cranial defects. (* = Significant differences p < 0.001). Reproduced from [39] with permission from the Royal society for Chemistry.