Justine C. Lee, Paul S. Cederna
As we reflect on 75 years of experimental publications in Plastic and Reconstructive Surgery, a few thoughts come to mind. The first is how far we have come as a field. Investigations have progressed from simple observations of the natural history of transferred tissue to mechanistic descriptions of intracellular alterations and the integration of emerging technologies in reconstructive procedures. The second is the astonishing breadth of the field. Essentially, plastic surgery has laid claim to all of human anatomy and its associated functions, yet we are constrained to none. The third is the pervasive sense of exhilaration in exploration. Perhaps the reason for the latter is that plastic surgery has always been a specialty defined by autonomy of thought in pursuit of solutions, unified only by the central objective of structural and functional restoration. Thus, the inherent nature of the specialty is one that is built on fundamental research and continually evolves through innovation and discovery. On the seventy-fifth anniversary of Plastic and Reconstructive Surgery, we will discuss some of the major advances in plastic surgery research, highlight some landmark discoveries over the years, and, of course, mention some of our personal favorites. Tissue Transfer and Transplantation In the first issue of Plastic and Reconstructive Surgery in 1946, Lyndon Peer published his innovative and unconventional experiments to better understand the growth of pediatric cartilage grafts.1 To do this, he implanted autogenous cartilage grafts, from various anatomical locations, into infants and children and explanted them a few years later. From these experiments, he concluded that the cartilage grafts grew: maybe. As unusual as it may have been to perform these experiments, particularly in infants and children, he was pursuing one of the primary areas of interest in plastic surgery investigation: the quest to understand the impact of tissue transfer and remodeling. In the 1940s to 1950s, the ideas of moving autologous or homologous tissues were simultaneously developing. Early studies in vascularized autologous tissue transfer were focused on methods to improve flap vascularity and techniques to monitor flap perfusion. From a historical perspective, one of our favorite advances during this period was the repurposing of Millikan’s ear oximeter, originally designed for pilots during World War II and credited as the origin of modern pulse oximetry, for perfusion monitoring of pedicled flaps following transfer.2 Regarding autologous tissue transfer, perhaps the most consequential advance occurred in 1957, when Harry J. Buncke developed techniques for transferring blocks of tissue on 1-mm vessels. He subsequently demonstrated successful replantation of digits and ears in animal models (Fig. 1).3 Shortly after the first report by Buncke, Goldwyn observed that viability of large, pedicled island flaps was improved with microvascular anastomoses, predicting the possibility of free tissue transfer.4 These pioneers of microsurgery sparked a decade of microsurgical advances starting with the proof-of-principle demonstration by Krizek et al. of the first abdominal musculocutaneous free flaps in a canine model,5 followed by the introduction of functional free flaps with neurotization by Tamai et al.,6 and the addition of bone by Ostrup and Fredrickson,7 culminating in clinical translation in 1973.8Fig. 1.: The birth of microsurgery. Before the work by Buncke and Schulz in 1965, salvage of amputated fingers was attempted by means of grafting of either composite tissues or osseous components under a pedicled flap. During the late 1950s and 1960s, the increase in understanding of transferring tissues on microanastomoses suggested that replantation of an entire digit may be possible. Thus, Buncke and Schulz designed a set of animal experiments using a rhesus monkey model to best imitate human finger replantation. In their series of nine experimental replantations, only one survived (experiment 6, animal 5). However, the success of this one experiment was the proof-of-principle result that opened the field of microsurgery. Vessel clamped and measured at 0.8 mm in diameter (above, left); microanastomosis (below, left). Experiment 6 at 2 weeks after surgery (center) and animal 5 with replanted finger at 3 months after surgery (right). (Reprinted with permission from Buncke HJ, Schulz WP. Experimental digital amputation and reimplantation. Plast Reconstr Surg. 1965;36:62–70.)Simultaneously, consideration of allogeneic sources for tissue transfer was expanding in the postwar era, with an emphasis on methods of banking skin allografts9 and reducing allograft rejection with varying techniques such as radiation therapy and steroid administration.10,11 After the reports from Murray et al. regarding renal allotransplantation,12,13 attention shifted to vascularized composite tissues, converging with the gains in microsurgical techniques. One of the first attempts at understanding vascularized composite allotransplantation was performed by Goldwyn et al. in 1966 using canine limbs (Fig. 2).14 Although all of the allotransplants in this study ultimately failed, they demonstrated that rudimentary immunosuppression delayed rejection. Remarkably, they also observed that different tissue types exhibited variable rejection rates, astutely foreshadowing the work by Lee et al. in 1991 demonstrating differences in antigenicity of tissue types.15 Over the course of the 1970s to 1990s, progressive developments in the understanding of free flap perfusion16–20 and transplant immunology21–26 gradually reduced the morbidity in autologous transfer, increased the functionality of autologous transfer, and culminated in clinical translation of vascularized composite allotransplants.Fig. 2.: Early vascularized composite allotransplantation. Unlike replantation, few attempts at understanding extremity allotransplantation were occurring until the 1960s. Inspired by a clinical report of a failed extremity allotransplant, Goldwyn and colleagues sought to understand the effects of immunosuppression in their seminal study of canine limb allotransplantation. Although all of the transplants were ultimately rejected, the authors demonstrated that immunosuppression delayed rejection reliably and that tissue types varied in their rates of rejection. Shown is a femoral arteriogram of an azathioprine-treated canine limb allotransplant at postoperative day 18 with patent distal arteries. (Reprinted with permission from Goldwyn RM, Beach PM, Feldman D, Wilson RE. Canine limb homotransplantation. Plast Reconstr Surg. 1966;37:184–195.)Synthesizing Tissue and Creating Function The second exciting area of plastic surgery investigation was focused on the idea of synthesizing tissue and creating function. The major differences between the two areas of investigation are that the latter has a rebellious streak, breaking all the rules of nature by creating function in an area devoid of function; plastic surgery is still in its infancy in this area. Although the idea of synthesizing tissue is age-old, the ability to do so has been very challenging. The first attempt to synthesize tissue was presented in Plastic and Reconstructive Surgery in 1952 by Kathryn Lyle Stephenson, who implanted cartilage extracts into rodent muscles and supplemented them with hormones to create ectopic cartilage.27 Unfortunately, these experiments were unsuccessful, but they stimulated a series of novel experiments that would ultimately become the field of regenerative medicine. The ensuing two decades saw few investigations in regenerative medicine until the exceptional work of Snyder et al. in 1973, where they described successful mandibular distraction osteogenesis in a canine model (Fig. 3).28 These experiments were ultimately translated into the clinical arena by McCarthy et al. 20 years later.29 The study by Snyder et al., in concept, is one of our favorites in that distraction was and continues to be one of the only examples of completely endogenous, clinically useful, surgically practical tissue synthesis.Fig. 3.: Regenerating bone. Although gains in clinical knowledge have occurred for both autologous and homologous tissue transfer, tissue synthesis has yet to enter the clinical arena in a substantial manner, with the exception of distraction osteogenesis. Inspired by the ideas of lengthening bones, Snyder et al. hypothesized that the same concepts could be applied to the facial skeleton. In a canine model, Snyder and colleagues surgically created a shortened mandible such that a severe crossbite was present. After 6 weeks of healing, the authors osteotomized the mandible and placed an external fixator (left) that was lengthened at a rate of 1 mm/day for 14 days and consolidated for 6 weeks. At the end of the consolidation period, a radiograph was taken (right) demonstrating bony healing. This pilot experiment by Snyder and colleagues in 1973 eventually led to the clinical translation of mandibular distraction by McCarthy et al. and is one of the only examples of tissue synthesis that has reached the clinical realm. (Reprinted with permission from Snyder CC, Levine GA, Swanson HM, Browne EZ Jr. Mandibular lengthening by gradual distraction: Preliminary report. Plast Reconstr Surg. 1973;51:506–508.)During the 1980s, the idea that biological tissue could be synthesized by artificial materials started to crystallize. One of the most significant additions to the literature during that period was the description and eventual conceptual clinical translation of an artificial biomaterial guiding peripheral nerve regeneration in a rat sciatic nerve model by Seckel et al. (Fig. 4)30 and in a nonhuman primate model by Dellon and Mackinnon.30,31 This concept was shortly followed by investigations on creating other tissues, such as cartilage,32 using the same strategy of synthetic, biodegradable polymers with incorporated cellular material. Vacanti and colleagues demonstrated the most dramatic example with the culturing and in vivo implantation of chondrocytes on a polymeric scaffold in the shape of an ear.33–35 However, despite the incredible enthusiasm generated by seeing human ears on the backs of nude mice, long-term stability in immunocompetent settings remains elusive.Fig. 4.: Guiding regeneration with materials. The 1980s were marked by an increasing interest in guiding regeneration with scaffolding materials. Two groups, Seckel et al. and Dellon and Mackinnon, demonstrated in two different animal models that peripheral nerve gaps could be successfully regenerated with the interposition of a resorbable polymeric nerve guide to span the gap. These studies ushered in a vast number of investigations using resorbable materials as an inert scaffold for delivery of trophic factors or cells for a variety of tissue types. Shown is the experimental design using rat sciatic nerve gaps as described by Seckel and colleagues. (Reprinted with permission from Seckel BR, Chiu TH, Nyilas E, Sidman R. Nerve regeneration through synthetic biodegradable nerve guides: Regulation by the target organ. Plast Reconstr Surg. 1984;74:173–181.)The concept of guiding tissue regeneration gained in popularity and became an area of intense investigation in the 1990s to 2000s. In particular, there was an explosion of interest in growth factors and growth factor delivery, especially bone morphogenetic proteins in the realm of bone regeneration.36–39 However, around 2009, it started to become clear that supraphysiologic dosages of growth factors were unlikely to be reasonable clinical solutions for regeneration. Although tissue could be regenerated, the complete lack of control over that regeneration, with no reliable approaches to stop that growth, created regulatory barriers to clinical translation.40 Particularly with the concurrent revelations on the complexity of calvarial suture biology by Roth et al.,41–44 the conclusion emerged that bone regeneration was unlikely to be accomplished by any one single factor but rather was the summation of multiple cues from a defined microenvironment. Over the past decade, technological advances at both the micro and macro levels have allowed us to truthfully ask the question of whether recapitulation of nature is absolutely necessary for functional restoration. At the micro level, efforts have shifted in the direction of fabricating microenvironments that may not be identical to the mature tissue itself, but the milieu necessary to generate the mature tissue over time. That is, single-tissue regeneration has evolved toward integrating sophisticated and tunable biomaterials tailored to globally organize multicellular responses with the goal of eliminating delivery of exogenous growth factors or ex vivo–expanded progenitor cells. The challenge now lies in detailed characterization of cell-material interactions. At the macro level, technological advances in engineering and robotics beg the question about whether functional replacement requires biological tissues. In the realm of limb loss, advances in prosthetics are arguably outpacing the possibilities of safe immunosuppression. In other words, design and implementation of the interfaces between biology and machinery may replace the need for transfer of composite biological tissues for optimal function.45–48 The evolution of the two major lines of plastic surgery investigation is truly a reflection of the spirit of plastic surgery, interrelated yet boundless in the incorporation of new ideas and fields of study. Ultimately, plastic surgery has always been the home for the creative people in medicine; the idealists who believe that there is a solution to everything; the eternal optimists who see zero limits, only challenges to be accepted; and the extraordinary people who rejected the mundane and instead chose the adventure (Fig. 5). We enthusiastically look forward to the evolution of the next 75 years, which are sure to be just as thrilling as the first.Fig. 5.: Over the past 75 years of experimental publications in Plastic and Reconstructive Surgery, investigations have progressed from simple observations of the natural history of transferred tissue to mechanistic descriptions of intracellular alterations and the integration of emerging technologies in reconstructive procedures. Plastic surgery has always been a specialty defined by autonomy of thought in pursuit of solutions, unified only by the central objective of structural and functional restoration. The inherent nature of the specialty is one that is built on fundamental research and continually evolves through innovation and discovery.