Restoration of Oral and Craniofacial Defects by Stem Cells and Bioengineering Approaches

The face distinguishes one human being from another. Through evolution, the human face is highly individualized compared with most other species. The facial tissues and organs are arguably the most complex in the human body, accommodating multiple functions of vision, hearing, smell, taste, touch, mastication, swallowing, and breathing. The face is a portal for the “inner self,” a source of self-recognition and attraction.

The face is considered to be harmonious if there is a high degree of symmetry between the left and right sides. When disfigurement of the face occurs from trauma, tumors, chronic diseases, or congenital deformities, the physical and psychosocial effects can be extremely detrimental. In 2000 the U.S. Surgeon General’s Report on Oral Health stated that a serious facial and oral disfigurement “may undermine self-image and self-esteem, discourage normal social interaction, and lead to chronic stress and depression as well as to incurring great financial cost.” Furthermore, facial and oral disfigurement “may interfere with vital functions such as breathing, eating, swallowing, and speaking. The burden of disease restricts activities in school, work, and home, and often significantly diminishes the quality of life.”

Several medical and dental specialties, including dentistry, orthodontics, maxillofacial prosthetics, prosthodontics, plastic and reconstructive surgery, ear-nose-throat surgery, and oral/maxillofacial surgery are devoted to the reconstruction of facial disfigurement. Sometimes, the complexity and diversity of the involved tissue phenotypes of dental, oral, and craniofacial defects require a multidisciplinary approach for reconstruction.

This chapter discusses the major clinical challenges in craniofacial reconstruction, outlines current clinical management approaches, and identifies emerging approaches in tissue engineering and stem cell biology toward biologically based reconstruction of dental, oral, and craniofacial defects. Because of limited space, only selected topics in oral and craniofacial diseases and biologically based reconstruction are discussed. The reader is referred to several insightful and more specialized reviews that have recently been published.

CLINICAL NEEDS FOR CRANIOFACIAL BONE AND SOFT TISSUE RECONSTRUCTION

Trauma/Injuries

According to the Centers for Disease Control and Prevention (CDC), more than 5 million individuals were admitted to the emergency department for facial trauma in 2005 in the United States. Facial trauma is considered any injury to the face, including skin lacerations, soft tissue injuries, obstruction to the nasal cavity or sinuses, damage to the orbital sockets, and fracture to the jawbone and teeth.

One of the common causes of oral and craniofacial trauma in children is playground-related injuries ( Table 28-1 ). Emergency departments in the United States treat more than 200,000 playground injuries each year for children age 14 years or younger. The total cost of treating these injuries is estimated at $1.2 billion.

TABLE 28-1
Facial trauma in young and elderly Populations, United States (Annual)
Age Causes Incidence (million) Cost (billions)
14 and younger Playground injuries 0.2 $1.2
65 and older Falls 1 $27
Data from Office of Technology Assessment, US Congress: Risks to students in school, Washington, DC, 1995, US Government Printing Office; and Englander F, Hodson TJ, Terregrossa RA: J Forensic Sci 41:733-746, 1996.

Among the elderly population, falls are the leading cause of injury deaths and the most common cause of injuries and hospital admissions for trauma ( Table 28-1 ). In the United States, one of every three persons age 65 years or older falls each year. The total cost of treating all fall injuries for this age group in 1994 was $27 billion. In 2002, almost 13,000 people age 65 and older died of fall-related injuries. As the number of people over age 65 rises from 31 million in 1990 to 68 million by 2040 in the United States, the cost of fall injuries is expected to increase to $44 billion (in current dollars). Although the frequency of facial injuries from falling is not high, even a small fraction of fall-related facial injuries can carry a significant cost.

According to the 2005 report of the American Society of Plastic Surgeons, reconstructive surgeries performed for trauma-related injuries (e.g., animal bite, burn care, laceration repair, maxillofacial surgery, scar revision) make up 13% of all reconstructive surgeries performed in the United States. Even though this report does not provide the statistics for facial trauma reconstruction, the economic consequence of facial trauma is significant because facial reconstruction often requires multiple surgeries.

Congenital Deformations

Cleft lip/palate

According to the National Center on Birth Defects and Developmental Disabilities, a division of the CDC, cleft lip/palate occurs in one of every 700 to 1000 live births and is the most common congenital malformations of the head and neck region. A cleft results from the failure of fusion of parts of the lip and/or palate during the early months of prenatal development. The etiology of cleft lip/palate is multifactorial, including genetic defects, nutritional deficiencies, maternal hypoxia, alcohol ingestion, and drug use. Certain medications during the first trimester of pregnancy may contribute to clefts.

Unilateral cleft lip, with or without cleft palate, is one of the most common birth defects in humans and is genetically distinct from isolated cleft palate. Relatively few candidate genes have been linked to nonsyndromic cleft lip/palate, although the genetic contribution to nonsyndromic orofacial clefts has been estimated at 20% to 50%. Unilateral cleft lip and palate occurs more commonly in males and more frequently on the left side. Patients with isolated cleft lip may also have a cleft of the anterior part of the maxillary alveolar process. Bilateral clefts and isolated clefts of the lip and palate are not uncommon. Other facial clefts also occur, much less frequently, involving the orbits, zygoma, and commissures of the lip clefts.

The goals of cleft lip/palate therapy are to restore function and improve esthetics. These difficult tasks require multiple interventions and careful coordination between different specialties. The craniofacial team usually consists of oral and maxillofacial surgeon, plastic surgeon, speech pathologist, pediatrician, pediatric dentist, orthodontist, otolaryngologist, and maxillofacial prosthodontist. Other critical members usually include nurses, feeding specialists, psychologists, geneticists, and a social worker.

The American Society of Plastic Surgeons reports that a total of 32,000 birth-defect reconstruction surgeries were performed in 2005, almost 19,000 of which were cleft lip/palate surgeries ( Table 28-2 ). One of the surgical guidelines is the “rule of 10s” before the lip repair. The infant weighs at least 10 pounds, has 10 mg/dL of hemoglobin, and is at least 10 weeks of age. The rule of 10s decreases the risk for anesthetic complications while allowing the doctors to perform additional tests to evaluate for cardiac, pulmonary, or renal abnormalities. Palate repair is usually performed in a single stage at 9 to 18 months of age to promote proper speech development. Additional surgical and dental procedures (orthognathic surgery, bone grafting, orthodontic treatment, pediatric dentistry, prosthodontic treatment) and nondental therapies (additional revision plastic surgery, speech therapy, swallowing therapy) are sometimes needed to address esthetic and functional concerns.

TABLE 28-2
Number of Reconstructive Surgeries for Congenital Craniofacial Defects, United States, 2005
Surgery Number
Birth defect reconstruction 32,000
Cleft lip/palate surgeries 19,000
Data from American Society of Plastic Surgeons, 2005.

Craniosynostosis

Craniosynostosis, the premature fusion of cranial sutures, is another common craniofacial birth defect, occurring in one of every 2500 live births. Premature fusion of one or more cranial sutures prevents subsequent cranial growth surrounding the fused cranial sutures while inducing excessive growth at patent sutures. The net result is craniofacial deformities. Craniosynostosis leads to abnormally high intracranial pressure, impaired cerebral blood flow, airway obstruction, impaired vision and hearing, learning difficulties, and adverse psychological effects. Surgical intervention is currently the only way to relieve intracranial pressure and reshape disfigured skull bones.

Tumors: Oral and Head and Neck Cancers

Each year in the United States, approximately 30,000 people are newly diagnosed with oral and pharyngeal cancer ( Table 28-3 ). Worldwide, approximately 350,000 to 400,000 oral cancer cases are reported each year, although these undoubtedly represent a fraction of all oral cancer cases. Although oral cancer only accounts for 2% to 4% of all cancers diagnosed annually in the United States, the survival rates of oral cancers are among the lowest of major cancers, according to the CDC. Only half of individuals diagnosed with oral cancers survive 5 years after diagnosis. In contrast to other cancers, such as breast, colorectal, and prostate, the overall U.S. survival rate from oropharyngeal cancer has not improved in the past 16 years. Oral cancer is twice as common in males as females, which is much different from the 5 : 1 male/female ratio about 40 years ago. Increased tobacco use among women is the main reason for the increases in oral cancer rates. Age is also a factor; 95% of oral cancers occur among persons older than 40, with 60 years the average age at diagnosis.

TABLE 28-3
Estimated New Cancer Cases and Deaths from Oropharyngeal Cancer, United States
Oral Cavity and Pharynx Estimated New Cases Estimated Deaths
Tongue 9,040 1,780
Mouth 10,230 1,870
Pharynx 8,950 2,110
Other oral cavity 2,770 1,670
total 30,990 7,430
Male
Female
20,180
10,810
Data from American Cancer Society: Cancer facts and figures, 2006.

Resection of oral cancer frequently results in severe disfigurement. The reconstruction of hard and soft tissues of the facial and oral structures is usually a demanding task. One of the key difficulties in reconstruction surgeries of oral cancer is shortage of tissue. Squamous cell carcinoma is the most common malignancy of the oral cavity, but minor salivary gland tumors, primary bone tumors, and tumors of dental origin also occur, with margins greater than 1 cm required to achieve disease control and wide, clear margins.

Chronic Diseases: Temporomandibular Joint Disorders

The National Institute of Dental and Craniofacial Research (NIDCR) of the National Institutes of Health (NIH) states that more than 10 million people in the United States have temporomandibular joint (TMJ) disorders, or jaw joint problems, at any given time. The total direct and indirect cost of TMJ-related disorders is unclear, but the CDC reports that the total cost of arthritis and other rheumatic conditions in the United States in 1997 was $86.2 billion. TMJ disorders include degenerative joint disease, which encompasses a variety of symptoms, including pain in the TMJ region, “joint noise,” and limitation of jaw motion. Severely affected patients often endure excruciating pain in everyday activities such as eating, yawning, and talking. In many patients the symptoms may be relieved by a combination of pain control medications, resting the jaw, adopting a soft diet, and applying heat to the muscles. If these conservative techniques are not effective, a clinician may have to consider more invasive procedures that involve replacing the jaw joints with artificial implants.

CURRENT CLINICAL APPROACHES IN RECONSTRUCTION OF CRANIOFACIAL DEFECTS

A wide range of the technical approaches are used to reconstruct disfigured dental, oral, and craniofacial structures including soft tissue grafting and bone grafting by means of autografts, allografts, and xenografts. Despite various levels of clinical success, these procedures are limited by donor site morbidity, limited tissue supply, immune rejection, and potential transmission of pathogens. Improved surgical reconstructive techniques include pedicled flaps and microvascular free-tissue transfers of composite flaps that can be designed to compensate for both hard and soft tissue deficits. These improved methods still necessitate significant morbidity, however, and the outcome of true form and function is still compromised.

Scientists and clinicians have also explored the field of growth factor therapy for treating patients with osseous defects. However, the limitations of growth factor therapy include rapid denaturation and diffusion of the factor, high cost, and potential toxicity.

In 2005, French surgeons performed the first face transplant for a female patient whose face was disfigured by dog attack. The risks of chronic immunosuppression, malignancy, and infection are the major downfall to this risky procedure. Face transplantation is also ethically controversial.

Maxillofacial prosthetics are used to restore extraoral and intraoral defects and often represent the least invasive approach. Currently, a myriad of maxillofacial prostheses are used in patients with defects resulting from cancer, trauma, or congenital anomalies. However, retention and stability of a large prosthesis may be difficult. Prosthetic devices can be combined with and can complement flap reconstruction. Microvascular free flaps have several benefits, as well as contraindications. Previous radiation therapy, previous neck surgery, ligation of the facial artery, and other insulting factors decrease the chance of flap survival. Difficulties in preserving rerouting and reimplanting arteries and salivary ducts need to be addressed. Donor site morbidity includes flap reliability, risk of nerve palsy, sensory deficits or intolerances, motor weakness, accessibility, functional impairment, and cosmetic issues. Patient occupation may preclude the use of certain donor sites. Tissues that are unhealthy, hair bearing, or in esthetic zones limit potential site selection and outcome. Donor tissue cannot be harvested from sites where this will aggravate facial asymmetry and distort or disrupt overall facial dynamics.

Reconstruction of Tongue Defects

The tongue plays a vital role in speech, swallowing, and mastication and is intimately related to the mandible, dentition, neck, and larynx. Most tongue defects result from surgically resected carcinomas, although traumatic defects are not uncommon after gunshot wounds.

Partial glossectomy reconstruction

Common procedures and flaps for anterior oral tongue reconstruction include primary closure and secondary reepithelialization for smaller defects. Larger defects are restored by allografts, autografts, and regional myocutaneous flaps. For more substantial defects, free-tissue fasciocutaneous transfers from the radial forearm, lateral arm and thigh, and scapula and abdominal free flaps are used for partial to near-total glossectomies. Prosthodontic treatment for partial glossectomies is necessary only when the patient experiences difficulty in speaking or managing a food bolus. Either a palatal or a mandibular augmentation prosthesis may be fabricated. The function of the augmentation prosthesis is to fill the volume deficiency between the remaining tongue and the mandible and palate.

Ventral tongue and floor of mouth reconstruction

The floor of the mouth is the second most common defect after the tongue. Tumor size and characteristics will determine the extent of the resection and type of reconstruction modality. Full-thickness grafts from areas of redundant tissue and split-thickness grafts from areas such as the lateral thigh can be used. Survival of the graft relies on neovascularization, and therefore the recipient bed and the graft must be in good condition and rendered immobile to promote capillary neogenesis. Radiated tissue represents a poor recipient bed, and grafts are contraindicated or likely to fail. Platysma myocutaneous flap can also be used, especially if the defect is continuous with the neck.

For extensive soft tissue reconstruction in the oral cavity, the radial forearm free flap has become immensely popular because it can be shaped to approximate most defects and contains healthy vascular supply with venous outflow. The radial forearm free flap (RFFF) provides thin, pliable, and predominantly hairless tissue with reliable vascularity. Overall success rate is reported to be 97%. The volar tissue provides large pedicles with nerve anastomosis. Closure of the donor site is accomplished using a split-thickness skin graft. The potential for morbidity of the donor site, the extended operative time, and technical expertise required in free-tissue reconstruction should be weighed during evaluation.

Reconstruction of base of tongue and total glossectomy defects

In almost 70% of oropharyngeal cancers, the base of the tongue is involved. Five-year survival rates for stage 1 and 2 disease remain at 80%. Early-stage tumors are treated by surgery or radiation. Reconstruction is difficult because of inherently compromised tissue. Local control with combined-modality treatment is higher, at 60%. Small to partial base-of-tongue defects can involve primary closure to fasciocutaneous (radial, ulnar, and lateral arm) or myocutaneous pedicled flap (pectoralis major). Subtotal to total glossectomy defects can be addressed with an array of these flaps, including those from the latissimus dorsi, anterolateral thigh, and scapular areas.

Resection of any part of the tongue affects deglutition (swallowing function), articulation (speech intelligibility), and aspiration (airway protection) and compromises motor and sensory function. Functional tongue reconstruction has remained a challenge because of the complex motor function involved in normal deglutition and articulation. Although some current reconstruction techniques employ motor innervation, little if any coordinated muscle function results from these methods. Donor site morbidity, prolonged surgery, and limited collaborative resources may preclude the preferential treatment with microvascular free flaps. Current tongue flaps may severely compromise tongue mobility and thus speech and swallowing.

Defects of Buccal Mucosa and Salivary Ducts

Reconstructive options for the buccal mucosa and salivary ducts usually involve the use of split-thickness skin grafts. These grafts have low patient donor site morbidity but can experience significant graft contracture and scar band formation at the mucosal junction. The use of acellular human collagen matrix (Alloderm, Lifecell Corporation, Branchburg, N.J.) has also been described for the reconstruction of mucosal defects. Preserving the elasticity of the buccal mucosa is advantageous because large scar bands may significantly hinder jaw opening, mastication, and mobilization of the food bolus.

The most common reconstructive method for buccal mucosa is the RFFF, with a success rate of up to 95%. However, the deficiencies of RFFF include the lengthy recovery time, rehabilitation of the forearm, and high demand for microvascular expertise. Other free-tissue transfers are possible using the lateral arm, latissimus dorsi, rectus abdominus, and lateral thigh to fill in buccal defects that may arise from resection of the buccinator muscle and buccal fat, which leads to hollowing of the midface if left unreconstructed.

Hard Palate Reconstruction

The hard palate is essential to separating the oral cavity from the nasal and sinus cavities, thus allowing proper phonation and articulation, as well as breathing and chewing. Hard palate defects result in the oral cavity, maxillary sinus, and nasal cavity becoming one confluent chamber. Maxillofacial prostheses have a primary role in reconstruction of palatal defects by obturating the cavity, sealing the palate, and providing dentition. Prosthetic intervention, when desired, should occur at surgery, and surgical enhancements can maximize the prosthetic outcome and patient acceptance.

To maximize retention and stability of the prosthesis, as much of the hard palate and dentition as possible should be retained. The premaxillary region enhances stability and support and is extremely important in minimizing the fulcrum of prosthesis into the defect and, if preserved, reduces the collapse of the facial form and postoperative contracture. The medial margin of the defect should be covered with palatal mucosa for added tolerance and stability. Similarly, a split-thickness skin graft is recommended to cover the denuded surfaces of the cheek to reduce healing time, prevent the migration of respiratory epithelium, and allow for a keratinized denture-bearing surface. A lateral scar band will occur at the junction of the skin graft with the remaining buccal mucosa, attributed to providing retention through an anatomical undercut. A split-thickness skin graft can also be applied to the sinus walls, thus providing additional area for retention and reducing mucus production. In larger defects, removal of the inferior turbinate is also recommended to allow for the medial wall of the obturator bulb to extend into the nasal cavity. The additional height counters rotation of the prosthesis during function.

A surgical obturator should be provided immediately at resection to act as a matrix for the surgical dressing and permit speech and swallowing postoperatively, often eliminating the need for a nasogastric tube. In addition, the obturator prevents oral contamination of the surgical site while psychologically assisting the patient by restoring normal palatal contours. Screws, sutures, or ligature wire can be used initially to secure the prosthesis. An interim obturator is delivered 1 week later and can be customized to enhance stability, retention, and esthetics. After the resected area has stabilized (6-12 months later), a final obturator prosthesis is fabricated.

Various pedicled autogenous tissues have been described to correct palatal defects but may be limited by the lack of tissue bulk, length of vascular pedicle, and need for multiple stages of reconstruction to achieve the final result. Alternatively, microvascular free-tissue transfer offers adequate amounts of bone and soft tissue bulk that can be transferred in a single-stage procedure. Various free-tissue transfers, including myocutaneous, myofacial, and osteocutaneous flaps, can be used for reconstruction of the palate and midface. The radial forearm, latissumus dorsi, rectus abdominus, scapular, fibular, and iliac crest flaps are most often used.

The thin, pliable tissue characteristics of the RFFF allow the palate to be sealed and to serve as a potential surface for dentures. In addition, the radial bone can be used to recreate the maxillary arch and can support osseointegrated implants. Radial bone can reconstruct the premaxillary area and thus help support the upper lip and nasal base. The scapular osteocutaneous flap has the advantage of a soft tissue component that can be rotated around adequate vascularized bone and can support implants. This is especially advantageous in the edentulous patient who requires a dental prosthesis. The fibular free flap and the iliac crest free flap tissue transfers have been shown to have an adequate column of bone to support osseointegrated implants.

Surgical reconstruction of large defects may fail to reproduce palatal contour, which adversely affects bolus control and speech. Also, bulky flaps may prevent placement of an intraoral prosthesis.

Reconstruction of Cleft Lip/Palate

Complex congenital deformities such as cleft lip and palate have significant physical and psychological effects and require multidisciplinary management. Timing of repair and reconstructive options depend on severity and extent of the deformity, consideration of speech development, facial growth, psychological effects, and safety of anesthesia. Various palatoplasty approaches have been described, including two-flap palatoplasty for complete unilateral and bilateral clefts, three-flap palatoplasty for incomplete clefts, and double-reversing Z -plasty for submucosal clefts and incomplete secondary palate clefts.

Although plastic surgery has made great advances in the area of cleft surgery, surgical repair cannot alone solve the multiple problems encountered with the deformities that result from cleft lip and palate. Creation of an esthetically acceptable columnella and the deformity of nasal cartilages are especially difficult. Prosthetic intervention with a presurgical nasoalveolar molding device (PNAM) addresses these problems using an intraoral plate and nasal extension that dynamically repositions the deformed nasal cartilages and alveolar processes while lengthening the deficient columnella. Continual modifications to this appliance ameliorate the initial cleft nasal deformity and can eliminate the need for surgical correction of the columnella while minimizing the extent of scarring of the oronasal complex. Possible disadvantages of the PNAM include soft tissue breakdown when forces exceed tissue tolerances. Success of the appliance is based on parental compliance and dedicated, consistent, and proper use of the device. When used in conjunction with a modified surgical approach, the PNAM allows for a single initial surgical procedure to address the lip-nose-alveolar complex and its deformity, and it decreases the number of future corrective surgeries.

For cleft palate patients who have not been surgically treated, the anterior nasal communication is addressed using an obturator, as previously described. Often a patient with an unrestored cleft palate presents with complicated occlusion issues, including an undesirable maxillomandibular relationship. Teeth adjacent to the defect may be compromised because of poor bone quality and should be splinted for preservation. The patient requires fabrication of a removable partial denture or a complete denture prosthesis that will simultaneously repair the defect, restore the continuity to the premaxilla, ensure occlusal function, and create an esthetic appearance.

EMERGING APPROACHES: STEM CELLS AND TISSUE ENGINEERING

Oral and craniofacial defects have a high demand for multiple tissue phenotypes and frequently present with many complex issues for reconstruction. Current approaches for facial reconstruction are limited by several intrinsic deficiencies. For example, autologous tissue grafts necessitate donor site morbidity; prostheses do not integrate with host tissues; and allogeneic and other grafts are associated with immune incompatibility and potential pathogen transmission. Clinicians and scientists have attempted to restore facial defects with the patient’s own stem cells in approaches that minimize current deficiencies such as donor site morbidity, immunorejection, pathogen transmission, and suboptimal repair. Recent studies have demonstrated the proof of the principle of using stem cells in the reconstruction of dental, oral, and craniofacial defects.

Large-scale tissue-engineering research, in craniofacial or other areas, began in the early 1990s after the discovery of stem cells that not only can self-renew, but also are capable of differentiating into multiple cell lineages. So far, substantial advances have been made in tissue engineering because of advances in seemingly unrelated disciplines, including cell and molecular biology, polymer chemistry, molecular genetics, materials science, robotics, and mechanical engineering, converged into the self-assembling field of tissue engineering.

Stem Cells

The complex three-dimensional form of the face arises from the growth and fusion of several embryonic primordia. The middle and upper regions of the face are derived from the frontonasal process, the cheeks and upper portion of the jaw from the paired maxillary primordia, and the lower aspects of the jaw from the mandibular primordia. These primordia are populated by mesenchymal cells that are multipotent and capable of differentiating into osteoblasts, chondrocytes, adipocytes, and fibroblasts. Mesenchymal cells are derivatives of embryonic stem cells, a few hundred cells of the inner mass of the blastocyst. Embryonic stem cells differentiate into neural crest cells that in turn migrate to form facial primordia.

What is the difference between the mesenchymal cells and the mesenchymal stem

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Jun 4, 2016 | Posted by in Orthodontics | Comments Off on Restoration of Oral and Craniofacial Defects by Stem Cells and Bioengineering Approaches
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