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The face distinguishes one human being from another. When the face is disfigured because of trauma, tumor removal, congenital anomalies, or chronic diseases, the patient has a strong desire for functional and esthetic restoration. Current practice of facial reconstruction using autologous grafts, synthetic fillers, and prostheses is frequently below the surgeon's and patient's expectations. Facial reconstruction is yet to take advantage of recent advances in seemingly unrelated fields of stem cell biology, chemical engineering, biomaterials, and tissue engineering. “Biosurgery,” a new concept that we propose, will incorporate novel principles and strategies of bioactive cues, biopolymers, and/or cells to restore facial defects. Small facial defects can likely be reconstructed by cell homing and without cell transplantation. A critical advantage of cell homing is that agilely recruited endogenous cells have the potential to harness the host's innate capacity for regeneration, thus accelerating the rate of regulatory and commercialization processes for product development. Large facial defects, however, may not be restorable without cell delivery per our understanding at this time. New breakthrough in biosurgery will likely originate from integrated strategies of cell biology, cytokine biology, chemical engineering, biomaterials, and tissue engineering. Regardless of cell homing or cell delivery approaches, biosurgery not only will minimize surgical trauma and repetitive procedures, but also produce long-lasting results. At the same time, caution must be exercised against the development of products that lack scientific basis or dogmatic combination of cells, biomaterials, and biomolecules. Together, scientifically derived biosurgery will undoubtedly develop into new technologies that offer increasingly natural reconstruction and/or augmentation of the face.
The human face becomes highly individualized during development. Orofacial tissues are arguably the most complex in the human body, accommodating multiple functions of vision, hearing, smell, taste, touch, chewing, speech, swallowing, and breathing. When the face is disfigured because of trauma, tumor resection, infectious diseases, or congenital anomalies, the physical and psychosocial effects are 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.”1
The prevalence of facial defects is summarized in Table 1.2–6 A myriad of congenital anomalies, such as cleft lip, cleft palate, hemifacial microsomia, and craniosynostosis, adversely affect the face. Facial trauma remains one of the most common injuries in war and peacetime and frequently presents as challenges for both esthetic and functional restorations. Chronic diseases result in dental, oral, and craniofacial defects. Postablative head and neck cancer patients frequently have significant functional disabilities and a poor esthetic outcome.
Facial defects are currently restored by the patient's own (autologous) tissue grafts, allogeneic tissue grafts, xenogenic tissue grafts, synthetic materials, or prosthesis.2 Autologous tissue grafts invariably necessitate donor site morbidity. For example, a patient missing a segment of the maxilla or mandible frequently experiences additional trauma, pain, and morbidity because of an autologous bone graft harvested from the donor site such as the ileum. Similarly, a patient's missing portion of the nose after facial trauma or skin cancer resection may be reconstructed by an autologous skin and soft tissue graft from the forehead, which creates additional scarring and disfigurement. Autologous grafts are often considered the clinical gold standard, because allografts, xenografts, and synthetic materials are associated with complications such as pathogen transmission, immune rejection, and suboptimal integration.7–12 However, a key drawback of autologous tissue grafting is donor site morbidity.13–15
In addition to the burden of reconstruction of facial defects, there is an increasing demand for facial augmentation or rejuvenation.13–15 Facial augmentation or rejuvenation is frequently achieved by repetitive injections of fillers of naturally derived tissue analogs or synthetic materials.16 For example, injectables are used to correct contour deformities and rhytids due to loss of soft tissue or aging. Current injectable fillers include collagen (xenografts and allograft), freeze-dried acellular dermal tissue, calcium hydroxyapatite spheres, and polymer beads of poly-l-lactic acid (PLLA) and polymethylmethacrylate (PMMA). Such injectables must be host compatible and not cause immunogenic, inflammatory, or carcinogenic effects. Current fillers are frequently short lasting and require repetitive injections. The long-lasting polymer injectables such as PMMA or PLLA may be associated with clumping and foreign body reaction.17 Moreover, current injectables suffer from suboptimal integration with host tissue, premature degradation, and suboptimal remodeling with surrounding host tissue.
Dermal tissue can potentially be restored by an intricate combination of extracellular matrix fibers including collagen and elastin. Accordingly, extracellular matrix-based materials have been extensively used as acellular soft tissue fillers, including collagen-based homologs such as purified human collagen (CosmoDerm/CosmoPlast, Inamed Gauting, Germany), decellularized processed dermal allograft (Cymetra LifeCell Corporation, Branchburg, NJ), particulate fascia lata allograft (Fascian Fascia Biosystems, Los Angeles, CA), and xenogeneic materials such as bovine collagen (Zyderm/Zyplast [Allergan, Irvine, CA]). Bovine collagen has been widely used as injectable fillers.18 Most of these fillers can be injected readily as an in-office procedure. Given the xenogenic nature of bovine collagen, there are safety considerations including potential pathogen transmission and immunorejection. Even with normal skin tests, approximately 3% of patients develop foreign body reactions.18 Most natural fillers degrade within short periods of time after injection and necessitate repetitive injections.
Other naturally occurring human extracellular matrix substances, such as hyaluronic acid (HA), have also been extensively used in facial augmentation. HA in the skin is commonly depolarized with aging, leading to reduced ability to retain water.18 Thus, replenishing HA may improve skin appearance by rehydrating the subcutaneous tissue. Compared with collagen, HA lasts somewhat longer but still requires repeated injections.
Alloplastic materials may address some of the deficiencies associated with short actions of natural substances. Alloplastic materials include hydroxyapatite particles embedded in a highly viscous gel (Radiesse BioForm Medical, San Mateo, CA), PLLA microparticles (Sculptra Sanofi-aventis U.S., Bridgewater, NJ), and PMMA microspheres (Artecoll Pulmon Medical, Natal, South Africa). The role of tissue engineering in facial reconstruction or rejuvenation is to promote the use of biocompatible materials with or without biomolecules or cells that allow host tissue to remodel and achieve the desired characteristics. Optimally, the injectables should induce cellular ingrowth while undergoing degradation at a well-balanced rate. There has been little progress in the translation of tissue engineering approaches to the clinical setting of soft tissue reconstruction or augmentation, despite meritorious effort. The delivery of chemokines or cytokines that induce cell homing is likely to reach the clinical market before cell-based applications, because cell delivery may require ex vivo manipulations, training of current clinical practitioners on cell handling, and other undesirable features such as excessive cost and potential contamination.
The premise of this review is that collective advances in stem cell biology, cytokine biology, chemical engineering, biomaterials, and tissue engineering, especially in the past decade, have established the foundation for “biosurgery,” a new paradigm for facial reconstruction and augmentation. Biosurgery is based on the principles and practice of the delivery of bioactive cues, biopolymers, and/or cells that are tailored to restore facial defects, circumventing the typically short-term, nonregenerative practice of current facial filler procedures (Fig. 1). It is probable based on the existing experimental data that restoration of small facial defects or augmentation can be achieved by cell homing and without cell transplantation (Fig. 1). At this time, the restoration of large facial defects may still rely on cell delivery (Fig. 1). Biological regeneration of orofacial tissues overcomes most, if not all, of the drawbacks of autologous grafting or artificial materials. Undoubtedly, the end is near for current clinical practice of autologous, allogeneic, and xenogenic grafting. The projected advances in the coming years of facial reconstruction and/or augmentation will likely stem from integrated strategies of cell biology, cytokine biology, chemical engineering, biomaterials, and tissue engineering. A number of challenges need to be further addressed before broad applications of biosurgery in facial reconstruction and augmentation: Would it be possible to heal certain facial defects by cell homing and without cell transplantation in patients? How to induce cell homing? Are autologous cells always necessary? Can allogeneic cells or xenogenic cells be safely transplanted to heal facial defects? What are the scientific and business barriers associated with cell transplantation or cell homing approaches? Here, we will discuss some of these critical questions.
Cell-based therapies have been considered a key ingredient in the anticipated era of personalized medicine. In this context, diseased, ageing, missing, or traumatized cells or tissues are to be healed by autologous cells, as opposed to autologous tissue grafts that can only be harvested with sizable donor site morbidity. Autologous tissue grafts, the current surgical “gold standard,” are harvested from one part of the patient's body for the reconstruction of another part. Compared with autologous tissue grafts, one of the key advantages of cell-based therapies is to minimize donor site morbidity.19,20 For example, a patient who has a bone graft harvested from the iliac crest for facial reconstruction experiences donor site morbidity of the iliac crest. Early attempts of therapeutic cell delivery have adopted the concept that cells in diseased tissues were to be replaced by like cells that are healthy.19,20 For example, it has been thought for some time that degenerating arthritic cartilage has to be repaired by healthy chondrocytes. A number of drawbacks have become apparent in association with early attempts of autologous cell therapies. First, sufficient numbers of healthy donor cells are scarce and therefore cannot be obtained without inducing donor site trauma that neither the surgeon nor the patient desires to have. A patient with cardiac infarct has no autologous donor site for the restoration of the infarcted area. Second, delivered cells without carriers sometimes migrate away from the intended location or transform into undesirable cells. For the regeneration of structural tissues such as bone or cartilage, cell delivery without carriers fails because of a lack of the obligatory structural and mechanical support. Third, the delivered end-stage cells, because of programmed cell death or necrosis, are often incapable of regenerating or maintaining the volume or the function of target tissues. Allogeneic grafts and xenogenic grafts are derived from human or nonhuman species, respectively. Despite the advantage of no donor site morbidity, the major disadvantages of allogeneic or xenogenic grafts can be substantial, including potential immunorejection, pathogen transmission, and mismatch of color and texture.21–25 Synthetic materials have endless supply but may suffer from the reported suboptimal integration, leakage, foreign body reaction, or extrusion and dislocation.26,27
Autologous adipose tissue has been transplanted to fill soft tissue defects. A drawback of autologous soft tissue grafts, besides donor site morbidity, is postoperative volume reduction.12,28 Volume reduction after autologous fat transfer can be as high as 70%.21–32 Volume reduction following fat grafts or adipose cell transfer procedures may be due to apoptosis of the transplanted mature adipocytes, their low tolerance to ischemia, and slow revascularization rate.32 Single-cell suspension of mature adipocytes isolated from lipectomy or liposuction aspirates has been incorporated in scaffolds and transplanted to fill soft tissue defects. However, postoperative volume reduction of tissues from lipectomy-isolated adipocytes is a major barrier for patient satisfaction.9,12,18,29,30 In addition, adipose grafts from liposuction aspirates may be associated with suboptimal blood supply and necrosis of the graft.32 The yield of adipocytes in lipectomy aspirates is usually low because of a variety of factors including mechanical damage.32 Mature adipocytes are fully differentiated and undergo apoptosis, leading to a common shortage of adipocytes for soft tissue reconstruction.33
Stem/progenitor cells may overcome the deficiencies of autologous tissue grafts or end-stage cells. For example, mesenchymal stem cells, which are progenitors of subcutaneous soft tissue, can be isolated from bone marrow, adipose tissue, or other sources.19,20 These stem/progenitor cells are capable of multiple population doublings, therefore potentially serving as a replenishable source for facial soft tissue reconstruction.14,22,34 The field of facial reconstruction and augmentation has yet to take full benefit of the fruit of stem cell biology, cytokine biology, chemical engineering, materials science, and tissue engineering. Many studies, including those exemplified below, have provided some of the ground works necessary for biosurgery in relation to facial reconstruction and/or augmentation:
Although the era of biosurgery for facial reconstruction and augmentation is on the horizon, caution must be exercised against product development without sound scientific data or dogmatic combination of cells, biomaterials, and growth factors. Despite temporary hype, products not based on the proof of efficacy and safety are likely short lived.37 Dogmatic combinations of cells, biomaterials, and growth factors have a tendency to yield a level of complexity that gives rise to new ideas for scientific experiments, but, at the same time, may be prohibitive for product development (Fig. 2).
The process of cell transplantation for generating adipose tissue grafts has been explored.20,36,38–43 A key issue of vascularization in bioengineered soft tissue has been addressed in a number of meritorious studies.39–41 For example, we demonstrated that a biophysical approach of building microchannels and/or delivery of bioactive cues such as basic fibroblast growth factor (bFGF) induces host-derived angiogenesis in bioengineered adipose tissue grafts.36 Remarkably, microchannels in a hydrogel system were shown to serve as conduits for host-derived blood vessels with or without an angiogenic growth factor, bFGF.36 In another example, mesenchymal stem cells were transplanted to the surfaces of the orofacial bone, yielding new bone that changed the contour of the facial appearance in mouse and swine.43 Pending issues for the reconstruction of soft tissues, including the face and breast, by the approach of cell transplantation are as follows:
Cell homing has been regarded as a process of exit of hematopoietic stem cells from blood vessels by transendothelization and subsequent migration. Here we broadly define cell homing as active recruitment of endogenous cells, including stem/progenitor cells, into an anatomic compartment. Cell homing differs from current filler injections. Most facial fillers do not allow cell homing or even passive cell ingrowth. Fillers further lack mechanisms for active recruitment of cells. In contrast, cell homing-based facial reconstruction or augmentation relies on the recruitment of endogenous cells with novel scaffold characteristics and/or bioactive cues. We postulate that certain facial tissue defects can be healed by cell homing and without cell transplantation (Fig. 2). Cell homing offers a number of advantages over cell transplantation for facial reconstruction and/or augmentation:
A number of bioactive cues that participate in adipogenesis have been adopted in soft tissue engineering, including insulin-like growth factors (IGFs), epidermal growth factor, transforming growth factor β, platelet-derived growth factor, insulin, thyroid hormone, and dexamethasone. For example, bFGF adsorbed to Matrigel promotes adipogenesis in vivo.44 Matrigel contains high quantities of laminin-1, an extracellular protein that is preferential for preadipocyte adhesion and may act synergistically with bFGF to induce adipogenesis.45,46 In addition to bFGF, insulin and IGF-I have important functions during adipogenic differentiation. Ectopic islands of adipose tissue in deep muscular fascia of rat abdominal wall are generated upon local delivery of insulin and IGF-I by polylactic glycolic acid (PLGA)/poly (ethylene)-glycol microspheres within 4 weeks.47 We have recently demonstrated the combinatory effects of chemical and physical cues during adipogenic tissue engineering. Delivery of bFGF via poly(ethylene)-glycol-diacrylate hydrogel that contain physical microchannels induced host-derived angiogenesis in adipose tissue grafts by guided host tissue infiltration.36 The delivery of adipogenic and angiogenic factors have promising prospects in transforming otherwise inert and limited reconstructive soft tissue fillers into bioactive and long-lasting substitutes. In development, multiple bioactive cues are expressed in specific temporospatial patterns. Do these temporospatial patterns during natural development need to be recapitulated in therapeutic wound healing or regeneration? This is an open question that warrants serial investigations. Conceptually, it is probably neither necessary nor practical in tissue repair to replicate the temporospatial expression of myriads of bioactive cues that are expressed in development. Nonetheless, microencapsulation and controlled release of bioactive cues offer technical approaches to deliver pivotal bioactive cues in timed courses and in gradients that are most effective.47–50 Delivery of bioactive cues by in vivo injection is associated with rapid denaturation and diffusion.47 For example, we previously showed that controlled release of transforming growth factor β3 over time in vivo restored the morphogenesis of an otherwise synostosed cranial suture and generated a patent mesenchymal/fibrous tissue interface between cranial bones.50
Biosurgery promises not only to minimize surgical trauma and repeated procedures, but also produce native tissue analogs that are long lasting. New breakthrough will likely originate from integrated strategies of cell biology, cytokine biology, biomaterials, chemical engineering, and tissue engineering approaches. Several examples of interdisciplinary approaches have been provided in this review. First, cell homing by bioactive cues offers an unprecedented opportunity for near-term translation of biologically based therapies for facial reconstruction and augmentation. Second, the critical issue of angiogenesis has been addressed by biophysical approaches such as microchannels and biological approaches such as angiogenic growth factors. Third, scale up, another critical issue for soft tissue regeneration, is being addressed by a number of innovative approaches including modularized bioscaffolds that promote angiogenesis and cell survival. The exciting era of human facial reconstruction is yet to come, but the end is near for current widespread clinical practice of tissue grafting, fillers, and prosthesis.
The authors thank Sarah Kennedy and Fen Guo for administrative and technical assistance. This research was supported by NIH grants DE015391 and EB006261 (to J.J.M).
No competing financial interests exist.