Innovative Molecular and Cellular Therapeutics in Cleft Palate Tissue Engineering

Abstract

Clefts of the lip and/or palate are the most prevalent orofacial birth defects occurring in about 1:700 live human births worldwide. Early postnatal surgical interventions are extensive and staged to bring about optimal growth and fusion of palatal shelves. Severe cleft defects pose a challenge to correct with surgery alone, resulting in complications and sequelae requiring life-long, multidisciplinary care. Advances made in materials science innovation, including scaffold-based delivery systems for precision tissue engineering, now offer new avenues for stimulating bone formation at the site of surgical correction for palatal clefts. In this study, we review the present scientific literature on key developmental events that can go awry in palate development and the common surgical practices and challenges faced in correcting cleft defects. How key osteoinductive pathways implicated in palatogenesis inform the design and optimization of constructs for cleft palate correction is discussed within the context of translation to humans. Finally, we highlight new osteogenic agents and innovative delivery systems with the potential to be adopted in engineering-based therapeutic approaches for the correction of palatal defects. Impact statement Tissue-engineered scaffolds supplemented with osteogenic growth factors have attractive, largely unexplored possibilities to modulate molecular signaling networks relevant to driving palatogenesis in the context of congenital anomalies (e.g., cleft palate). Constructs that address this need may obviate current use of autologous bone grafts, thereby avoiding donor-site morbidity and other regenerative challenges in patients afflicted with palatal clefts. Combinations of biomaterials and drug delivery of diverse regenerative cues and biologics are currently transforming strategies exploited by engineers, scientists, and clinicians for palatal cleft repair.

Keywords: cleft palate; craniofacial; drug delivery; polymer scaffold; regenerative surgery; tissue engineering.

FIG. 1.

Key developmental stages of palatogenesis. Around the fourth week of human development, cNCCs migrate from the dorsal edge of the rostral neural tube to form the frontonasal prominence and the paired maxillary and mandibular processes that surround the primitive oral cavity. This allows the nasal pits to take form and subsequently develop into paired medial and lateral nasal processes from the frontonasal prominence by week 5. The medial nasal processes then merge with the maxillary processes to form the upper lip and primary palate while bilateral outgrowths from the maxillary processes, termed the palatal shelves, grow vertically along either side of the tongue. At week 7, mandibular growth is evident and results in the descent of the tongue and the elevation of the palatal shelves to a more horizontal position. Further growth leads to formation of the midline epithelial seam and onset of palatal fusion. By week 10 of gestation, the secondary palate fuses with the primary palate and nasal septum, allowing palatal mesenchyme to differentiate into bony and muscular elements. These fusion processes of primary and secondary palate components are complete by week 12 of development, by which time the secondary palate is divided along the anterior/posterior axis into the bony hard palate and the soft palate that is more muscular in nature. cNCCs, cranial neural crest cells.

FIG. 2.

Veau classification of cleft lip and palate defects. Group (class) I. Defects of the soft palate only; Group II. Defects involving the hard palate and soft palate; Group III. Defects involving the soft palate to the alveolus, usually involving the lip; and Group IV. Complete bilateral clefts.

FIG. 3.

Surgical treatment staging timeline of cleft repair. (A) Lip closure through muscular alignment typically occurs by about 3 months of age; Following the “Rule of 10’s”: Hb = 10, 10 lbs body weight, 10 weeks of age. If the cleft lip is particularly wide, often adhesion is performed before lip closure. (B) In the range of 9–18 months of age, the soft palate is typically closed, as recovery of speech (consonant formation) is the primary concern around this age. If soft palate is closed before 9 months of age, the patient may be at risk for midfacial hypoplasia. (C) By 5–7 years of age, surgical repair of velopharyngeal incompetence is performed, often through superior-to-inferior pharyngeal flap elevation. Also, at this stage the surgeon can correct the nasal and/or lip deformities resultant following primary lip repair. (D) In the range of 7–12 years of age, the alveolar cleft defect is repaired, with exact timing dependent upon eruption of dentition (preferably performed during the mixed stage, when canine root is 2/3 formed). Approximately 95% of maxillary growth is completed by age 8 years. Following preoperative maxillary expansion, grafting procedure (either iliac crest bone graft or allograft) is performed to regenerate palatal bone. (E) As the patient progresses into adolescence and early adulthood, orthognathic corrective surgery (dependent on sex and gender) is often undergone. Males typically experience complete mandibular growth by age 21–23, while females typically are fully developed in the craniofacial complex by 2 years postpuberty. Corrective rhinoplasty is typically performed at this stage in conjunction with maxillary advancement to correct midface hypoplasia and/or dental malocclusion. Hb, hemoglobin.

FIG. 4.

Postnatal tissue engineering approaches for cleft palate regeneration. Upon diagnosis of palatal cleft, either prenatally or perinatally, an array of nonautologous regenerative therapies exist to couple osteoinductive growth factors, mesenchymal stem cells, and patient-specific scaffold-based delivery vehicles to the site of implantation. Properly timed within the mixed dentition stage of craniofacial development (∼7–12 years of age), such osteogenic therapies have the capacity to mitigate the need for autologous bone harvesting, decrease operative time, and overall costs, as well as improve surgical outcomes.