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Regenerative Medicine and Nasal Surgery

      Abstract

      Nasal surgery is a constellation of operations that are intended to restore form and function to the nose. The amount of augmentation required for a given case is a delicate interplay between patient aesthetic desires and corrective measures taken for optimal nasal airflow. Traditional surgical techniques make use of autologous donor tissue or implanted alloplastic materials to restore nasal deficits. Limited availability of donor tissue and associated harvest site morbidity have pushed surgeons and researchers to investigate methods to bioengineer nasal tissues. For this article, we conducted a review of the literature on regenerative medicine as it pertains to nasal surgery. PubMed was searched for articles dating from January 1, 1994, through August 1, 2014. Journal articles with a focus on regenerative medicine and nasal tissue engineering are included in this review. Our search found that the greatest advancements have been in the fields of mucosal and cartilage regeneration, with a growing body of literature to attest to its promise. With recent advances in bioscaffold fabrication, bioengineered cartilage quality, and mucosal regeneration, the transition from comparative animal models to more expansive human studies is imminent. Each of these advancements has exciting implications for treating patients with increased efficacy, safety, and satisfaction.

      Abbreviations and Acronyms:

      FGF (fibroblast growth factor), FTSG (full-thickness skin grafting), TGF (transforming growth factor)
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      Learning Objectives: On completion of this article, you should be able to (1) summarize the role of regenerative medicine in treating the anatomical and functional deficits that affect the nose, (2) differentiate the benefits and drawbacks of various tissue engineering techniques when applied to distinct nasal subsites, and (3) recognize areas in need of further investigation prior to clinical application.
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      In their editorial and administrative roles, William L. Lanier, Jr, MD, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry.
      The authors report no competing interests.
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      Nasal surgery is a constellation of operations that are intended to restore form and function to the nose. In general, nasal surgery can be described as operations on the septum, rhinoplasty of the external nasal structures, and nasal reconstruction in cases of traumatic or oncological tissue loss. In many patients, there is some overlap between these categories. Regardless of the categorization, it is often necessary to either replace missing tissue or augment what is there. The amount of augmentation required for a given case is a delicate interplay between patient aesthetic desires and corrective measures taken for optimum nasal airflow. From a surgical perspective, the nose can be considered a 3-layer structure with an inner, middle, and outer layer. The inner layer of the nose and paranasal sinuses is lined by pseudostratified epithelium consisting of ciliated and nonciliated columnar cells, basal cells, and goblet cells.
      • Fokkens W.J.
      • Lund V.J.
      • Mullol J.
      • et al.
      European Position Paper on Rhinosinusitis and Nasal Polyps 2012.
      • Yan Y.
      • Gordon W.M.
      • Wang D.-Y.
      Nasal epithelial repair and remodeling in physical injury, infection, and inflammatory diseases.
      This layer is covered by the middle layer of nasal framework that is made of bone in the upper third and cartilage in the lower two-thirds of the nose. The nasal skin is the outermost layer in this schema. Single or multilayer defects each present different challenges for the rhinoplasty surgeon.
      Traditional surgical techniques make use of autologous donor tissue or implanted alloplastic materials to restore nasal deficits.
      • Angelos P.C.
      • Been M.J.
      • Toriumi D.M.
      Contemporary review of rhinoplasty.
      Limited availability of donor tissue and associated harvest site morbidity have pushed surgeons and researchers to investigate methods to bioengineer tissues to restore each of the 3 nasal layers.
      • MacNeil S.
      Progress and opportunities for tissue-engineered skin.
      • Watson D.
      • Reuther M.S.
      Tissue-engineered cartilage for facial plastic surgery.
      Having unlimited bioengineered tissue that is immune tolerant, concomitant with the ability to incorporate different types of tissues into composite grafts, is imminently on the horizon for nasal reconstruction. The prospect of these advances is an exciting development.
      The field of regenerative medicine has made great advances over the past several decades. Although we have yet to bioengineer complex, multitissue, 3-dimensional nasal constructs, researchers have made important strides toward growing bioengineered tissue both in vitro and in vivo.
      • MacNeil S.
      Progress and opportunities for tissue-engineered skin.
      • Orlando G.
      • Baptista P.
      • Birchall M.
      • et al.
      Regenerative medicine as applied to solid organ transplantation: current status and future challenges.
      In this article, our goal is to review the current regenerative medicine literature as it pertains to nasal surgery. We will discuss the regenerative medicine and tissue engineering literature as it applies to reconstruction of different nasal defects.

      Septal Perforations and Other Mucosal Defects

      Nasal mucosa is a complex epithelial lining that serves many functions.
      • Yan Y.
      • Gordon W.M.
      • Wang D.-Y.
      Nasal epithelial repair and remodeling in physical injury, infection, and inflammatory diseases.
      Trauma to this protective lining may be self-inflicted as a result of trauma caused by digital manipulation or foreign bodies. Underlying inflammatory causes such as sarcoidosis, Churg-Strauss syndrome, granulomatosis with polyangiitis, and lupus can also precipitate damage to nasal mucosa, sometimes even resulting in nasoseptal perforation. The same can be said of infectious causes such as invasive fungal rhinosinusitis or rhinocerebral mucormycosis, tuberculosis, leprosy, and syphilis. Malignancies such as lymphoma or toxins such as cocaine, sulfuric acid vapor, glass dust, mercurials, and phosphorus can also be associated with such damage. Even medications such as vasoconstrictive nasal sprays or intranasal corticosteroid sprays can be damaging under certain circumstances. However, proliferative cells in the mucosa harbor incredible regenerative capacity and can restore mucosa in large defects without surgical intervention.
      • Yoshimura E.
      • Majima A.
      • Sakakura Y.
      • Sakakura T.
      • Yoshida T.
      Expression of tenascin-C and the integrin α9 subunit in regeneration of rat nasal mucosa after chemical injury: involvement in migration and proliferation of epithelial cells.
      • Khalmuratova R.
      • Jeon S.-Y.
      • Kim D.W.
      • et al.
      Wound healing of nasal mucosa in a rat.
      Although nasal mucosa has great regenerative potential, repeated insults, iatrogenic interventions to control epistaxis, systemic inflammatory diseases, or radiation for head and neck malignant neoplasms can impair the mucosa’s ability to heal. This can result in septal perforation or synechiae. Thus, septal perforations that increase to greater than 2 cm are too big for the mucosa to heal and commonly require local flap or free tissue reconstruction. Examples of such flaps include facial artery musculomucosal flaps, inferior turbinate pedicled flaps, tunneled sublabial mucosal flaps, and even radial forearm free flaps.
      • Mobley S.R.
      • Boyd J.B.
      • Astor F.C.
      Repair of a large septal perforation with a radial forearm free flap: brief report of a case.
      • Ayshford C.A.
      • Shykhon M.
      • Uppal H.S.
      • Wake M.
      Endoscopic repair of nasal septal perforation with acellular human dermal allograft and an inferior turbinate flap.
      • Friedman M.
      • Ibrahim H.
      • Ramakrishnan V.
      Inferior turbinate flap for repair of nasal septal perforation.
      • Heller J.B.
      • Gabbay J.S.
      • Trussler A.
      • Heller M.M.
      • Bradley J.P.
      Repair of large nasal septal perforations using facial artery musculomucosal (FAMM) flap.
      • Kilty S.J.
      • Brownrigg P.J.
      • Safar A.
      Nasal septal perforation repair using an inferior turbinate flap.
      • Barry C.
      • Eadie P.A.
      • Russell J.
      Radial forearm free flap for repair of a large nasal septal perforation: a report of a case in a child.
      Although larger septal perforations pose a reconstructive challenge, smaller perforations can be addressed by garnering the regenerative potential of the nasal mucosa itself. A straightforward technique for the repair of septal perforations is the use of acellular dermis (AlloDerm) as a bioscaffold that can be placed as an interposition graft to allow healing of the defect via secondary intention (Figure 1).
      • Lee K.C.
      • Lee N.H.
      • Ban J.H.
      • Jin S.M.
      Surgical treatment using an allograft dermal matrix for nasal septal perforation.
      We have had success with this technique in closing both singular defects up to 2 cm and multiple small perforations less than 2 cm. Successful perforation closure is upward of 90% using this technique in patients without impediments to wound healing such has corticosteroid use, atherosclerosis, diabetes mellitus, and use of tobacco products (A.S., J.R.J., G.S.H., H. Diggleman, MD, unpublished data, 2014).
      Figure thumbnail gr1
      Figure 1Acellular dermis placement technique.
      In addition to using the regenerative properties of adjacent nasal mucosa, there have been notable endeavors to bioengineer mucosal tissue that can address these defects. Most of these efforts have used the regenerative potential of fibroblasts and respiratory epithelial cells.
      • Goto Y.
      • Noguchi Y.
      • Nomura A.
      • et al.
      In vitro reconstitution of the tracheal epithelium.
      • Le Visage C.
      • Dunham B.
      • Flint P.
      • Leong K.W.
      Coculture of mesenchymal stem cells and respiratory epithelial cells to engineer a human composite respiratory mucosa.
      • Lee M.K.
      • Yoo J.W.
      • Lin H.
      • et al.
      Air-liquid interface culture of serially passaged human nasal epithelial cell monolayer for in vitro drug transport studies.
      • Kobayashi K.
      • Nomoto Y.
      • Suzuki T.
      • et al.
      Effect of fibroblasts on tracheal epithelial regeneration in vitro.
      The development of a graft that can support vascular ingrowth with subsequent proliferation of fibroblasts and epithelial cells is complex, relying chiefly on the use of a biodegradable scaffold that can retain shape during this process. Several synthetic and natural scaffolds have been tested in vitro and in vivo for optimal growth of respiratory epithelium, although no consensus exists on which is the best material for surgical implantation.
      • Goto Y.
      • Noguchi Y.
      • Nomura A.
      • et al.
      In vitro reconstitution of the tracheal epithelium.
      • Le Visage C.
      • Dunham B.
      • Flint P.
      • Leong K.W.
      Coculture of mesenchymal stem cells and respiratory epithelial cells to engineer a human composite respiratory mucosa.
      • Doolin E.J.
      • Strande L.F.
      • Sheng X.
      • Hewitt C.W.
      Engineering a composite neotrachea with surgical adhesives.
      • Kojima K.
      • Bonassar L.J.
      • Roy A.K.
      • Mizuno H.
      • Cortiella J.
      • Vacanti C.A.
      A composite tissue-engineered trachea using sheep nasal chondrocyte and epithelial cells.
      • Sachs L.A.
      • Finkbeiner W.E.
      • Widdicombe J.H.
      Effects of media on differentiation of cultured human tracheal epithelium.
      • Omori K.
      • Nakamura T.
      • Kanemaru S.
      • et al.
      Regenerative medicine of the trachea: the first human case.
      • Kobayashi K.
      • Suzuki T.
      • Nomoto Y.
      • et al.
      Potential of heterotopic fibroblasts as autologous transplanted cells for tracheal epithelial regeneration.
      • Macchiarini P.
      • Jungebluth P.
      • Go T.
      • et al.
      Clinical transplantation of a tissue-engineered airway.
      • Huang T.-W.
      • Chan Y.-H.
      • Cheng P.-W.
      • Young Y.-H.
      • Lou P.-J.
      • Young T.-H.
      Increased mucociliary differentiation of human respiratory epithelial cells on hyaluronan-derivative membranes.
      • Kobayashi K.
      • Suzuki T.
      • Nomoto Y.
      • et al.
      A tissue-engineered trachea derived from a framed collagen scaffold, gingival fibroblasts and adipose-derived stem cells.
      • Remlinger N.T.
      • Czajka C.A.
      • Juhas M.E.
      • et al.
      Hydrated xenogeneic decellularized tracheal matrix as a scaffold for tracheal reconstruction.
      To date, much of the work on mucosal regeneration has been directed toward restoring tracheal epithelial lining. Because the nasal cavity is lined by the same respiratory epithelium, tracheal mucosalization research and restoration techniques are directly applicable to nasal mucosa.
      • Kojima K.
      • Bonassar L.J.
      • Roy A.K.
      • Mizuno H.
      • Cortiella J.
      • Vacanti C.A.
      A composite tissue-engineered trachea using sheep nasal chondrocyte and epithelial cells.
      • Noruddin N.A.A.
      • Saim A.B.
      • Chua K.H.
      • Idrus R.
      Human nasal turbinates as a viable source of respiratory epithelial cells using co-culture system versus dispase dissociation technique.
      Successful regeneration of any tissue, including nasal mucosa, requires bioscaffolding, a cell source (be it ingrowth of local cells or seeding of cells), bioactive materials (such as growth factor to induce cell differentiation into a certain tissue type), and a microenvironment similar to the desired tissue type. In the realm of bioscaffolding, many researchers have used a collagen to aid in mucosal regeneration and healing.
      • Doolin E.J.
      • Strande L.F.
      • Sheng X.
      • Hewitt C.W.
      Engineering a composite neotrachea with surgical adhesives.
      • Omori K.
      • Nakamura T.
      • Kanemaru S.
      • et al.
      Regenerative medicine of the trachea: the first human case.
      • Kobayashi K.
      • Suzuki T.
      • Nomoto Y.
      • et al.
      Potential of heterotopic fibroblasts as autologous transplanted cells for tracheal epithelial regeneration.
      • Huang T.-W.
      • Chan Y.-H.
      • Cheng P.-W.
      • Young Y.-H.
      • Lou P.-J.
      • Young T.-H.
      Increased mucociliary differentiation of human respiratory epithelial cells on hyaluronan-derivative membranes.
      • Kobayashi K.
      • Suzuki T.
      • Nomoto Y.
      • et al.
      A tissue-engineered trachea derived from a framed collagen scaffold, gingival fibroblasts and adipose-derived stem cells.
      Collagen sponges and gels are suitable materials for cellular proliferation and differentiation but must be mechanically reinforced to prevent tearing during suturing. Kobayashi et al
      • Kobayashi K.
      • Suzuki T.
      • Nomoto Y.
      • et al.
      A tissue-engineered trachea derived from a framed collagen scaffold, gingival fibroblasts and adipose-derived stem cells.
      reinforced collagen sponges with polypropylene, then used collagen gel seeded with fibroblasts and adipocyte stem cells to bioengineer respiratory mucosa and cartilage in a rat model. Laboratory-prepared constructs were placed in tracheal defects, and a distinct layer of respiratory mucosa and cartilage was evident 2 weeks after in vivo implantation. In a human study, Omori et al
      • Omori K.
      • Nakamura T.
      • Kanemaru S.
      • et al.
      Regenerative medicine of the trachea: the first human case.
      used a crystalline polypropylene and high-density polyethylene mesh to reinforce a collagen sponge soaked in autologous venous blood to repair a tracheal defect. Two months postoperatively, the bioengineered graft was covered with mature respiratory mucosal tissue supported by mechanically sound cartilage.
      In addition to the success of heterologous collagen as a regenerative bioscaffold for respiratory mucosa, decellularized human trachea and other decellularized mammalian xenografts have also been found to promote reepithelialization of airway defects.
      • Macchiarini P.
      • Jungebluth P.
      • Go T.
      • et al.
      Clinical transplantation of a tissue-engineered airway.
      • Remlinger N.T.
      • Czajka C.A.
      • Juhas M.E.
      • et al.
      Hydrated xenogeneic decellularized tracheal matrix as a scaffold for tracheal reconstruction.
      It is universally accepted that 3-dimensional scaffolding more closely simulates the microarchitecture of extracellular matrix and is superior for tissue engineering when compared with 2-dimensional culture.
      • Nehrer S.
      • Spector M.
      • Minas T.
      Histologic analysis of tissue after failed cartilage repair procedures.
      • Walles T.
      • Giere B.
      • Macchiarini P.
      • Mertsching H.
      Expansion of chondrocytes in a three-dimensional matrix for tracheal tissue engineering.
      Natural materials such as decellularized tracheal tissue are efficacious but have several disadvantages, such as limited donor tissue availability and the need for a preemptive decellularization protocol.
      • Meezan E.
      • Hjelle J.T.
      • Brendel K.
      • Carlson E.C.
      A simple, versatile, nondisruptive method for the isolation of morphologically and chemically pure basement membranes from several tissues.
      • Baiguera S.
      • Damasceno K.
      • Macchiarini P.
      Detergent-enzymatic method for bioengineering human airways.
      A prolonged and complicated processing time carries with it an increased risk of pathogenic contamination.
      To date, numerous synthetic scaffolds have been developed to obviate the need for donor tissue and reduce processing time. However, a thorough literature search does not reveal any studies that perform a head-to-head comparison of different scaffolding materials and their effect on the rate of mucosal recovery or mechanical quality. Most synthetic materials eliminate the need for donor tissue and can be custom-made to provide structural integrity to a scaffold. As with any nonnative tissue, a synthetic scaffold can become infected and require removal. Many scaffold materials were originally used as suture material and in this form have been tested to be biocompatible. Scaffolding material is highly customizable, and normally biocompatible materials could cause an unwanted inflammatory response when implanted as a large scaffold.
      • Smith M.J.
      • Smith D.C.
      • White Jr., K.L.
      • Bowlin G.L.
      Immune response testing of electrospun polymers: an important consideration in the evaluation of biomaterials.
      More detailed testing is required to determine the immunogenicity of developing material. Therefore, it is important that any scaffolding material be carefully chosen to provide appropriate physical strength and minimize chances of an immune response. Synthetic material as a bioscaffold is available in addition to the collagen and decellularized tissue previously mentioned. Scaffolding selection is complex and dependent on pros and cons of each material.
      Successful endeavors in tissue regeneration of a single cell type have segued into multilayer constructs.
      • Pampaloni F.
      • Reynaud E.G.
      • Stelzer E.H.
      The third dimension bridges the gap between cell culture and live tissue.
      Accordingly, the potential for regenerative solutions to nasal disease states has expanded from singular mucosal defects and septal perforations to more elaborate processes such as empty nose syndrome (ENS). Empty nose syndrome is a constellation of symptoms that a patient experiences after aggressive resection of middle and/or inferior turbinates. The pathophysiology of ENS symptoms is poorly understood, but lack of turbinate nerve feedback and reduced surface area for moisturizing air have been suggested as possible etiologies.
      • Clarke R.W.
      • Jones A.S.
      • Charters P.
      • Sherman I.
      The role of mucosal receptors in the nasal sensation of airflow.
      Onset of symptoms can vary from months to years after initial operation. Symptoms typically consist of paradoxical nasal obstruction, nasal and pharyngeal dryness, feeling of suffocation, irritability, and even depression.
      • Coste A.
      • Dessi P.
      • Serrano E.
      Empty nose syndrome.
      Treatment of ENS is challenging because symptoms are often refractory. Mild symptoms are treated medically with nasal irrigations and nasal ointments to increase air humidification. Severe symptoms are treated surgically by submucosal implantation of graft material in the lateral nasal wall or the nasal septum. Numerous materials have been used to expand nasal tissue in treating ENS—muscle, bone, cartilage, biomaterials such as acellular dermis, and even hydroxyapatite.
      • Papay F.A.
      • Eliachar I.
      • Risica R.
      Fibromuscular temporalis graft implantation for rhinitis sicca.
      • Goldenberg D.
      • Danino J.
      • Netzer A.
      • Joachims H.Z.
      Plastipore implants in the surgical treatment of atrophic rhinitis: technique and results.
      • Rice D.H.
      Rebuilding the inferior turbinate with hydroxyapatite cement.
      • Moore E.J.
      • Kern E.B.
      Atrophic rhinitis: a review of 242 cases.
      • Jung J.H.
      • Baguindali M.A.
      • Park J.T.
      • Jang Y.J.
      Costal cartilage is a superior implant material than conchal cartilage in the treatment of empty nose syndrome.
      Autologous cartilage taken from the rib or auricle and bone grafts are associated with donor site morbidity, and alloplastic implants are prone to infection and extrusion. Mucosal regeneration, when combined with the cartilage tissue engineering techniques discussed in the next section, affords a feasible multilayer solution for restoring nasal surface area and moisture in efforts to treat this debilitating disorder. The current state of mucosal regeneration is summarized in Table 1.
      Table 1Summary of Mucosal Bioengineering Efforts
      ReferenceStudy typeYearScaffold materialCell typesBioactive materialStudy results
      Goto et al
      • Goto Y.
      • Noguchi Y.
      • Nomura A.
      • et al.
      In vitro reconstitution of the tracheal epithelium.
      In vitro1999Human amnionPig tracheal epithelial cells and pig tracheal fibroblastsHGF, EGF, and TGF-βInteractions with the amnion scaffold and fibroblasts and not growth factors promoted differentiation of respiratory epithelia
      Doolin et al
      • Doolin E.J.
      • Strande L.F.
      • Sheng X.
      • Hewitt C.W.
      Engineering a composite neotrachea with surgical adhesives.
      In vitro2002Polyethylene terephthalate membrane coated with collagen gel (Biocoat Insert)Human bronchial epithelial cells and human lung fibroblastsEGF, insulinFibrin glue (TISSEEL) was effective at joining bioengineered epithelium and bioengineered cartilage
      Le Visage et al
      • Le Visage C.
      • Dunham B.
      • Flint P.
      • Leong K.W.
      Coculture of mesenchymal stem cells and respiratory epithelial cells to engineer a human composite respiratory mucosa.
      In vitro2004Transwell polycarbonate membraneHuman bone marrow stem cells and human bronchial epithelial cellsTGF-β3Coculturing of respiratory epithelium and mesenchymal stem cells in chondrogenic culture can produce cartilage-like tissue lined by mature ciliary respiratory epithelium
      Kobayashi et al
      • Kobayashi K.
      • Suzuki T.
      • Nomoto Y.
      • et al.
      Potential of heterotopic fibroblasts as autologous transplanted cells for tracheal epithelial regeneration.
      In vitro2007Collagen gelRat tracheal epithelial cells and rat tracheal, dermal, nasal, and gingival fibroblastsEGF, insulinGingival fibroblasts and tracheal fibroblasts can induce respiratory epithelium differentiation and may accelerate mucosal defect healing
      Huang et al
      • Huang T.-W.
      • Chan Y.-H.
      • Cheng P.-W.
      • Young Y.-H.
      • Lou P.-J.
      • Young T.-H.
      Increased mucociliary differentiation of human respiratory epithelial cells on hyaluronan-derivative membranes.
      In vitro2010HYAFF (benzyl ester of hyaluronic acid covered with collagenMature respiratory epithelial cellsEGF, insulinHYAFF promotes mucociliary differentiation comparable to collagen
      Kojima et al
      • Kojima K.
      • Bonassar L.J.
      • Roy A.K.
      • Mizuno H.
      • Cortiella J.
      • Vacanti C.A.
      A composite tissue-engineered trachea using sheep nasal chondrocyte and epithelial cells.
      In vivo, nude mice2003Nonionic, surfactant polyol (Pluronic F-127)Sheep nasal septal respiratory epitheliaEGF, insulinNasal epithelia and cartilage cells can be used to regenerate native airway–like tissues
      Remlinger et al
      • Remlinger N.T.
      • Czajka C.A.
      • Juhas M.E.
      • et al.
      Hydrated xenogeneic decellularized tracheal matrix as a scaffold for tracheal reconstruction.
      In vivo, dogs2010Hydrated porcine decellularized matrixNone. Cells likely differentiated from naturally present basal cells in the scaffoldNoneHydrated decellularized matrix promoted development of mature airway epithelium but not cartilage
      Kobayashi et al
      • Kobayashi K.
      • Suzuki T.
      • Nomoto Y.
      • et al.
      A tissue-engineered trachea derived from a framed collagen scaffold, gingival fibroblasts and adipose-derived stem cells.
      In vivo, Sprague-Dawley normal rats2010Collagen sponge and polypropylene meshGingival fibroblasts and adipose tissue–derived stem cellsEGF, insulinAdipose stem cells and fibroblasts have a synergistic effect on respiratory epithelial regeneration
      Omori et al
      • Omori K.
      • Nakamura T.
      • Kanemaru S.
      • et al.
      Regenerative medicine of the trachea: the first human case.
      In vivo, human2005Crystalline polypropylene and high-density polyethylene mesh lined by collagen spongeAutologous venous blood injected into the sponge intraoperativelyNoneCollagen sponge provided scaffold over which complete defect reepithelialization occurred over 2 mo
      Macchiarini et al
      • Macchiarini P.
      • Jungebluth P.
      • Go T.
      • et al.
      Clinical transplantation of a tissue-engineered airway.
      In vivo, human2008Decellularized human donor tracheaBronchial respiratory cellsBovine pituitary extract, EGFBronchial respiratory epithelial cells formed normal tracheal mucosa on the inner surface of a decellularized tracheal graft
      EGF = epidermal growth factor; HGF = human growth factor; TGF = transforming growth factor.

      Cartilage Manipulation and Nasal Augmentation

      Optimal functional and aesthetic outcome in rhinoplasty requires meticulous donor cartilage shaping and constant subjective reevaluation of cartilage placement by the surgeon’s trained eye.
      • Toriumi D.M.
      Commentary on: Rhinoplasty: surface aesthetics and surgical techniques.
      Hence, it is important that bioengineered cartilage has mechanical properties similar to those of native autografts and can maintain its shape and properties in vivo after surgical shaping with a scalpel. Although it is important to generate cartilaginous structures in a specific shape (eg, ear and alar cartilage), it is equally, if not more, important to generate mechanically stable blocks/sheets of cartilage that can be manipulated intraoperatively.
      The most commonly used autologous donor sites for nasal augmentation are the cartilaginous nasal septum, auricular conchal bowl, and costal cartilage.
      • Sajjadian A.
      • Rubinstein R.
      • Naghshineh N.
      Current status of grafts and implants in rhinoplasty, part I: Autologous grafts.
      Nasal septal cartilage has the optimal mechanical properties but is limited in quantity and is often unavailable for those undergoing secondary procedures.
      • Richmon J.D.
      • Sage A.B.
      • Wong V.W.
      • et al.
      Tensile biomechanical properties of human nasal septal cartilage.
      • Richmon J.D.
      • Sage A.
      • Wong W.V.
      • Chen A.C.
      • Sah R.L.
      • Watson D.
      Compressive biomechanical properties of human nasal septal cartilage.
      • Westreich R.W.
      • Courtland H.W.
      • Nasser P.
      • Jepsen K.
      • Lawson W.
      Defining nasal cartilage elasticity: biomechanical testing of the tripod theory based on a cantilevered model.
      • Neuman M.K.
      • Briggs K.K.
      • Masuda K.
      • Sah R.L.
      • Watson D.
      A compositional analysis of cadaveric human nasal septal cartilage.
      Rib cartilage is sufficiently rigid to provide support and is available in sufficient quantities for reconstruction.
      • Alkan Z.
      • Yigit O.
      • Acioglu E.
      • et al.
      Tensile characteristics of costal and septal cartilages used as graft materials.
      Harvesting costal cartilage carries the risk of severe postoperative pain, pneumothorax, and damage to the intercostal neurovascular bundle. Additionally, improper carving technique can cause costal cartilage warping and lead to an unpredictable outcome in inexperienced hands.
      • Grellmann W.
      • Berghaus A.
      • Haberland E.J.
      • et al.
      Determination of strength and deformation behavior of human cartilage for the definition of significant parameters.
      Auricular cartilage is limited in quantity and has mechanical qualities inferior to those of nasal septal and rib cartilage.
      • Richmon J.D.
      • Sage A.
      • Wong W.V.
      • Chen A.C.
      • Sah R.L.
      • Watson D.
      Compressive biomechanical properties of human nasal septal cartilage.
      Hence, bioengineered cartilage with mechanical properties similar to those of nasal septal cartilage is poised to be an ideal source of tissue for nasal reconstruction.

      Bioengineered Cartilage Formation

      Efforts to bioengineer cartilage for rhinoplasty have mostly focused on creating material with properties mimicking those of nasal septal cartilage.
      • Grellmann W.
      • Berghaus A.
      • Haberland E.J.
      • et al.
      Determination of strength and deformation behavior of human cartilage for the definition of significant parameters.
      • Puelacher W.C.
      • Mooney D.
      • Langer R.
      • Upton J.
      • Vacanti J.P.
      • Vacanti C.A.
      Design of nasoseptal cartilage replacements synthesized from biodegradable polymers and chondrocytes.
      • Duda G.N.
      • Haisch A.
      • Endres M.
      • et al.
      Mechanical quality of tissue engineered cartilage: results after 6 and 12 weeks in vivo.
      • Kafienah W.
      • Jakob M.
      • Démarteau O.
      • et al.
      Three-dimensional tissue engineering of hyaline cartilage: comparison of adult nasal and articular chondrocytes.
      • Kamil S.H.
      • Kojima K.
      • Vacanti M.P.
      • Bonassar L.J.
      • Vacanti C.A.
      • Eavey R.D.
      In vitro tissue engineering to generate a human-sized auricle and nasal tip.
      • Chia S.H.
      • Schumacher B.L.
      • Klein T.J.
      • et al.
      Tissue-engineered human nasal septal cartilage using the alginate-recovered-chondrocyte method.
      • Haisch A.
      • Duda G.N.
      • Schroeder D.
      • et al.
      The morphology and biomechanical characteristics of subcutaneously implanted tissue-engineered human septal cartilage.
      • Mendelson A.
      • Ahn J.M.
      • Paluch K.
      • Embree M.C.
      • Mao J.J.
      Engineered nasal cartilage by cell homing: a model for augmentative and reconstructive rhinoplasty.
      • Reuther M.S.
      • Briggs K.K.
      • Neuman M.K.
      • Masuda K.
      • Sah R.L.
      • Watson D.
      Shape fidelity of native and engineered human nasal septal cartilage.
      Manufacturing tissue-engineered cartilage requires 4 components: a scaffold, chondrocytes or cells with chondrogenic potential to seed the scaffold, growth factors to promote mature cartilage formation, and environmental conditions mimicking cartilage’s natural site in the body.

      Scaffolds

      Several different scaffolds have been used to make de novo cartilage, but to our knowledge, no studies have found clear superiority of one material over others. Ideal scaffolding materials are porous in structure to house chondrocytes/stem cells, hydrophilic for optimal cell adherence to scaffolds, biocompatible and biodegradable, and nonimmunogenic. Alginate hydrogels and other hydrogel variants have good chondrogenic properties but cannot withstand suturing and are poor materials for direct implantation into the nose. The exception is when they are first grown into mature cartilage subcutaneously or in vitro.
      • Chia S.H.
      • Schumacher B.L.
      • Klein T.J.
      • et al.
      Tissue-engineered human nasal septal cartilage using the alginate-recovered-chondrocyte method.
      • Anseth K.S.
      • Bowman C.N.
      • Brannon-Peppas L.
      Mechanical properties of hydrogels and their experimental determination.
      • Kuo C.K.
      • Ma P.X.
      Ionically crosslinked alginate hydrogels as scaffolds for tissue engineering, part 1: Structure, gelation rate and mechanical properties.
      Some synthetic fiber scaffolds have generated concern for reduced graft cell viability.
      • Smith M.J.
      • Smith D.C.
      • White Jr., K.L.
      • Bowlin G.L.
      Immune response testing of electrospun polymers: an important consideration in the evaluation of biomaterials.
      • Kamil S.H.
      • Kojima K.
      • Vacanti M.P.
      • Bonassar L.J.
      • Vacanti C.A.
      • Eavey R.D.
      In vitro tissue engineering to generate a human-sized auricle and nasal tip.
      • Christophel J.J.
      • Chang J.S.
      • Park S.S.
      Transplanted tissue-engineered cartilage.
      • Hofmann S.
      • Knecht S.
      • Langer R.
      • et al.
      Cartilage-like tissue engineering using silk scaffolds and mesenchymal stem cells.
      Further studies are needed to fully define their long-term effect on graft cell survival and cartilage structure in immunocompetent hosts. Most in vivo studies are short term and use immunodeficient patients, making it difficult to draw conclusions about cell toxicity and inflammatory responses caused by synthetic fibers.
      Newer scaffold designs using poly(3-hydroxybutyrate-co-3-hydroxyvalerate), a biocompatible and biodegradable plastic produced by bacteria, has excellent potential for chondrogenesis and structural integrity.
      • Liu J.
      • Zhao B.
      • Zhang Y.
      • Lin Y.
      • Hu P.
      • Ye C.
      PHBV and predifferentiated human adipose-derived stem cells for cartilage tissue engineering.

      Sultana N, Wang M. PHBV Tissue engineering scaffolds fabricated via emulsion freezing/freeze-drying: effects of processing parameters. Paper presented at: 2011 International Conference on Biomedical Engineering and Technology (ICBET 2011); June 4-5, 2011; Kuala Lumpur, Malaysia.

      • Wu J.
      • Xue K.
      • Li H.
      • Sun J.
      • Liu K.
      Improvement of PHBV scaffolds with bioglass for cartilage tissue engineering.
      The drawbacks of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) are its brittleness and cost. Collagen sponges and other materials such has polyvinyl alcohol have also been described as promoting cartilage growth.
      • Mohajeri S.
      • Hosseinkhani H.
      • Ebrahimi N.G.
      • Nikfarjam L.
      • Soleimani M.
      • Kajbafzadeh A.M.
      Proliferation and differentiation of mesenchymal stem cell on collagen sponge reinforced with polypropylene/polyethylene terephthalate blend fibers.
      • Gonzalez J.S.
      • Alvarez V.A.
      Mechanical properties of polyvinylalcohol/hydroxyapatite cryogel as potential artificial cartilage.
      Novel scaffold designs using the aforementioned materials are developing rapidly. Electrospinning and 3-dimensional printing allow for precise control of scaffold design.
      • Li W.-J.
      • Tuli R.
      • Okafor C.
      • et al.
      A three-dimensional nanofibrous scaffold for cartilage tissue engineering using human mesenchymal stem cells.
      • Jeong C.G.
      • Hollister S.J.
      A comparison of the influence of material on in vitro cartilage tissue engineering with PCL, PGS, and POC 3D scaffold architecture seeded with chondrocytes.
      The impact of these novel scaffolds on cell viability, differentiation, and tissue structure continues to emerge.

      Cells and Growth Factors

      Scaffolds must be loaded with either mature chondrocytes or stem cells and growth factors for optimal cartilage formation. In vitro cartilage experiments must control environmental factors to closely match in vivo conditions. This is often done with bioreactors. Mature chondrocytes, adipose tissue–derived stem cells, and bone marrow–derived stem cells have all been used to generate cartilage.
      • Chia S.H.
      • Schumacher B.L.
      • Klein T.J.
      • et al.
      Tissue-engineered human nasal septal cartilage using the alginate-recovered-chondrocyte method.
      • Liu J.
      • Zhao B.
      • Zhang Y.
      • Lin Y.
      • Hu P.
      • Ye C.
      PHBV and predifferentiated human adipose-derived stem cells for cartilage tissue engineering.
      • Wu J.
      • Xue K.
      • Li H.
      • Sun J.
      • Liu K.
      Improvement of PHBV scaffolds with bioglass for cartilage tissue engineering.
      • Lin Y.
      • Luo E.
      • Chen X.
      • et al.
      Molecular and cellular characterization during chondrogenic differentiation of adipose tissue-derived stromal cells in vitro and cartilage formation in vivo.
      • Mehlhorn A.T.
      • Zwingmann J.
      • Finkenzeller G.
      • et al.
      Chondrogenesis of adipose-derived adult stem cells in a poly-lactide-co-glycolide scaffold.
      • Zhang J.
      • Liu L.
      • Gao Z.
      • et al.
      Novel approach to engineer implantable nasal alar cartilage employing marrow precursor cell sheet and biodegradable scaffold.
      • Zheng L.
      • Fan H.S.
      • Sun J.
      • et al.
      Chondrogenic differentiation of mesenchymal stem cells induced by collagen-based hydrogel: an in vivo study.
      • Chang A.A.
      • Reuther M.S.
      • Briggs K.K.
      • et al.
      In vivo implantation of tissue-engineered human nasal septal neocartilage constructs: a pilot study.
      Recently, adipose tissue–derived stem cells have gained favor over bone marrow stem cells because of the ease of harvest and abundant donor supply. Although undifferentiated stem cells can be used to make cartilage, some predifferentiation has been reported to produce histologically superior cartilage in the same amount of time.
      • Liu J.
      • Zhao B.
      • Zhang Y.
      • Lin Y.
      • Hu P.
      • Ye C.
      PHBV and predifferentiated human adipose-derived stem cells for cartilage tissue engineering.
      However, it remains to be seen if cartilage quality will be equal given enough time to develop in vivo.
      Cells are usually supplemented with growth factors to promote mature tissue formation. Transforming growth factors (TGFs) β1, β2, or β3 are used by most researchers. Fibroblast growth factors and bone morphogenic proteins also promote chondrogenesis. Although all 3 TGFs promote chondrogenesis, TGF-β2 and TGF-β3 are known to do so more potently than TGF-β1.
      • Barry F.
      • Boynton R.E.
      • Liu B.
      • Murphy J.M.
      Chondrogenic differentiation of mesenchymal stem cells from bone marrow: differentiation-dependent gene expression of matrix components.
      Kim and Im
      • Kim H.J.
      • Im G.I.
      Combination of transforming growth factor-beta2 and bone morphogenetic protein 7 enhances chondrogenesis from adipose tissue-derived mesenchymal stem cells.
      found that a combination TGF-β2 and bone morphogenic protein 7 potently promotes cartilage growth when used with adipose tissue–derived stem cells. Regardless of the type of cell used for chondrogenesis, growth factors are needed to maintain cell phenotype in culture and maximize tissue growth.

      Nasal Dorsal Augmentation

      Various methods exist to successfully augment the nasal dorsum, many of which include the use of bone, cartilage, or another material (Figure 2). Homologous and alloplastic materials have been used, each with their own advantages and disadvantages. Alloplastic materials such as silicone pose higher risk of infection and extrusion compared with autologous materials. However, autologous materials are limited in availability. In light of these limitations, researchers have attempted to generate autologous cartilage in more abundant supply. Yanaga et al
      • Yanaga H.
      • Yanaga K.
      • Imai K.
      • Koga M.
      • Soejima C.
      • Ohmori K.
      Clinical application of cultured autologous human auricular chondrocytes with autologous serum for craniofacial or nasal augmentation and repair.
      performed nasal dorsal augmentation in 32 patients using expanded auricular chondrocytes mixed with autoserum. Gel was injected into a subcutaneous pocket in the nasal dorsum and molded using finger pressure. Solid cartilage began to form after just 7 days of in vivo incubation. Histologic confirmation at 6 months revealed mature cartilage with perichondrium. There was an inconsequential donor site defect and excellent long-term aesthetic results at an average follow-up of 17 months. Although this method used in vitro–expanded mature chondrocytes, it is within our scientific capability to use adipose tissue–derived stem cells to completely avoid a cartilaginous donor site defect.
      Figure thumbnail gr2
      Figure 2Placement of graft (in red) for nasal dorsal augmentation.
      Advances have not been limited to chondrogenesis, however, with some studies also documenting the utility of osteogenesis for dorsal augmentation. A porous matrix of cross-linked bovine tendon collagen and glycosaminoglycan and decellularized bone matrix loaded with platelet growth factors have been successfully implemented. Small osseous nasal dorsum defects can be effectively augmented with decellularized bone matrix. Likewise, for larger defects, a porous matrix of cross-linked bovine tendon collagen and glycosaminoglycan can be used in the dorsum as a dermal bioscaffold and can provide up to 8 mm of height to the nasal dorsum.
      • Planas J.
      The use of Integra™ in rhinoplasty.

      Nasal Tip Augmentation and Cartilage Regeneration Efforts

      Given the body of research supporting the stable mechanical properties of bioengineered cartilage, it is the next logical step to use this material for nasal tip augmentation. Although gel chondrocyte augmentation of the nasal dorsum has been successfully attempted in humans, we are not aware of any human studies on the use of bioengineered cartilage for nasal tip augmentation. Table 2 includes some of the ongoing work with regenerative medicine as it pertains to rhinoplasty.
      Table 2Summary of Cartilage Bioengineering Efforts
      ReferenceStudy typeYearScaffold materialCell typesBioactive materialsStudy periodStudy results
      Kamil et al
      • Kamil S.H.
      • Kojima K.
      • Vacanti M.P.
      • Bonassar L.J.
      • Vacanti C.A.
      • Eavey R.D.
      In vitro tissue engineering to generate a human-sized auricle and nasal tip.
      In vitro2003PLGA with acrylic sheetsBovine articular cartilageHam F12 medium with fetal bovine serum12 wkMature neocartilage constructs can be produced into specific shapes entirely in vitro
      Reuther et al
      • Reuther M.S.
      • Briggs K.K.
      • Neuman M.K.
      • Masuda K.
      • Sah R.L.
      • Watson D.
      Shape fidelity of native and engineered human nasal septal cartilage.
      In vitro2013Alginate-reconstituted chondrocytes on polyester membrane insertsHuman nasal septal chondrocytesTGF-β1, FGF-2, FGF-10, PDGF-BB10 wkNeocartilage constructs had shape fidelity comparable to nasal septal cartilage
      Duda et al
      • Duda G.N.
      • Haisch A.
      • Endres M.
      • et al.
      Mechanical quality of tissue engineered cartilage: results after 6 and 12 weeks in vivo.
      In vivo, nude mice2000PLGABovine articular cartilageRPMI medium, without growth factors12 wkNeocartilage constructs had mechanical properties similar to human nasal septal cartilage after 12 wk of in vivo incubation
      Chang et al
      • Chang A.A.
      • Reuther M.S.
      • Briggs K.K.
      • et al.
      In vivo implantation of tissue-engineered human nasal septal neocartilage constructs: a pilot study.
      In vivo, nude mice2012Alginate-reconstituted chondrocytes on polyester membrane insertsHuman nasal septal chondrocytesTGF-β1, FGF-2, PDGF-BB2 moHistologic, biochemical, and biomechanical features of neocartilage resemble native human septal tissue
      Mendelson et al
      • Mendelson A.
      • Ahn J.M.
      • Paluch K.
      • Embree M.C.
      • Mao J.J.
      Engineered nasal cartilage by cell homing: a model for augmentative and reconstructive rhinoplasty.
      In vivo, Sprague-Dawley rats2014Alginate gelatin on PLGANoneTGF-β310 wkEmpty scaffolds loaded with growth factors induce chondrogenesis by cell homing when implanted into the nose
      Mehlhorn et al
      • Mehlhorn A.T.
      • Zwingmann J.
      • Finkenzeller G.
      • et al.
      Chondrogenesis of adipose-derived adult stem cells in a poly-lactide-co-glycolide scaffold.
      In vivo, nude mice2009PLGAHuman adipose tissue–derived stem cellsBasic FGF, TGF-β18 wkAdipose tissue–derived stem cells can successfully form cartilage in vivo
      Lin et al
      • Lin Y.
      • Luo E.
      • Chen X.
      • et al.
      Molecular and cellular characterization during chondrogenic differentiation of adipose tissue-derived stromal cells in vitro and cartilage formation in vivo.
      In vivo, nude mice2005Alginate gelHuman adipose tissue–derived stem cellsInsulin, TGF-β120 wkPredifferentiated adipose tissue–derived stem cells maintain differentiation and form cartilage in vivo
      Liu et al
      • Liu J.
      • Zhao B.
      • Zhang Y.
      • Lin Y.
      • Hu P.
      • Ye C.
      PHBV and predifferentiated human adipose-derived stem cells for cartilage tissue engineering.
      In vivo, nude mice2010PHBVHuman adipose tissue–derived stem cellsInsulin, TGF-β116 wkPredifferentiated adipose tissue–derived stem cells maintain differentiation and produce cartilage in vivo
      Wu et al
      • Wu J.
      • Xue K.
      • Li H.
      • Sun J.
      • Liu K.
      Improvement of PHBV scaffolds with bioglass for cartilage tissue engineering.
      In vivo, nude mice201390% PHBV/20% bioglassRabbit articular cartilageNone12 wkPHBV/bioglass scaffold makes superior cartilage in vivo compared with PHBV alone
      Yanaga et al
      • Yanaga H.
      • Yanaga K.
      • Imai K.
      • Koga M.
      • Soejima C.
      • Ohmori K.
      Clinical application of cultured autologous human auricular chondrocytes with autologous serum for craniofacial or nasal augmentation and repair.
      In vivo, human2006Chondrocytes suspended in autoserumHuman auricular chondrocytesNone3-34 moAuricular chondrocytes expanded in vitro form mature cartilage when injected in vivo into the nasal dorsum
      Planas
      • Planas J.
      The use of Integra™ in rhinoplasty.
      In vivo, human2011A porous matrix of cross-linked bovine tendon collagen and glycosaminoglycan, and demineralized bone matrixNonePDGF22-27 moDemineralized bone matrix and PDGF can be used to augment small osseous nasal dorsum defects. Integra can be used for larger defects and provides up to 8 mm of dorsum height by being replaced with dermis
      FGF = fibroblast growth factor; PDGF = platelet-derived growth factor; PHBV = poly(3-hydroxybutyrate-co-3-hydroxyvalerate); PLGA = poly(DL-lactide-co-glycolide); TGF = transforming growth factor.

      Nasal Skin Defects and Regenerative Medicine

      Nasal dermis defects due to neoplasm excision or trauma can be particularly challenging to excise and reconstruct. Local flaps and skin grafts are the mainstay of nasal skin cancer defect repair. Local flaps provide adequate skin color match but leave a visible donor site scar, even with superb surgical technique. Full-thickness skin grafting (FTSG) can also be used for defects not amenable to reconstruction by skin mobilization but its use is limited for larger defects. Very large cutaneous nasal defects mandate the use of interpolated flaps or even free tissue transfer for sufficient coverage. It can be challenging for patients requiring such procedures, as many trips to the operating room are often needed to restore the nose to some semblance of its original form and function. Often, complete restoration is an impossible task.
      Dermal bioscaffolds such as a porous matrix of cross-linked bovine tendon collagen and glycosaminoglycan have shown promise in skin regeneration with burns and large nevi excisions.
      • Dantzer E.
      • Braye F.M.
      Reconstructive surgery using an artificial dermis (Integra): results with 39 grafts.
      • Kopp J.
      • Magnus Noah E.
      • Rübben A.
      • Merk H.F.
      • Pallua N.
      Radical resection of giant congenital melanocytic nevus and reconstruction with Meek-graft covered Integra dermal template.
      • Kagan R.J.
      • Peck M.D.
      • Ahrenholz D.H.
      • et al.
      Surgical management of the burn wound and use of skin substitutes: an expert panel white paper.
      For nasal reconstruction, dermal bioscaffolds fall behind FTSG, local nasal flaps, nasolabial cheek flaps, and paramedian forehead flaps (Figure 3) in the reconstructive algorithm.
      • Planas J.
      The use of Integra™ in rhinoplasty.
      • Koenen W.
      • Felcht M.
      • Vockenroth K.
      • Sassmann G.
      • Goerdt S.
      • Faulhaber J.
      One-stage reconstruction of deep facial defects with a single layer dermal regeneration template.
      A porous matrix of cross-linked bovine tendon collagen and glycosaminoglycan and acellular dermis have been the most well described in rhinoplasty.
      • Planas J.
      The use of Integra™ in rhinoplasty.
      • Gryskiewicz J.M.
      Waste not, want not: the use of AlloDerm in secondary rhinoplasty.
      Tiengo et al
      • Tiengo C.
      • Amabile A.
      • Azzena B.
      The contribution of a dermal substitute in the three-layers reconstruction of a nose tip avulsion.
      described the use of a porous matrix of cross-linked bovine tendon collagen and glycosaminoglycan in conjunction with mucoperichondrial flap, cartilage graft, and delayed FTSG for a full-thickness nasal tip avulsion in which local flaps were not a viable option. Development of fully functioning color-matched bioengineered skin is still on the horizon.
      Figure thumbnail gr3
      Figure 3Paramedian forehead flap procedure.

      Conclusion

      The field of regenerative medicine is rapidly advancing and holds much promise for nasal surgery. The greatest advancements have been in the fields of mucosal and cartilage regeneration, with a growing body of literature to attest to its promise. With recent advances in bioscaffold fabrication, bioengineered cartilage quality, and mucosal regeneration, the transition from comparative animal models to more expansive human studies is imminent. Each of these advancements has exciting implications for treating patients with increased efficacy, safety, and satisfaction.

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