Review

Impact of surgical innovation on tissue repair in the surgical patient R. Tevlin1,2 , D. Atashroo1 , D. Duscher1 , A. Mc Ardle1,2 , G. C. Gurtner1 , D. C. Wan1 and M. T. Longaker1,2 1 Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Plastic and Reconstructive Surgery, and 2 Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA Correspondence to: Dr D. C. Wan, Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University Medical Center, 257 Campus Drive, Stanford, California 94305-5418, USA (e-mail: [email protected])

Background: Throughout history, surgeons have been prolific innovators, which is hardly surprising as

most surgeons innovate daily, tailoring their intervention to the intrinsic uniqueness of each operation, each patient and each disease. Innovation can be defined as the application of better solutions that meet new requirements, unarticulated needs or existing market needs. In the past two decades, surgical innovation has significantly improved patient outcomes, complication rates and length of hospital stay. There is one key area that has great potential to change the face of surgical practice and which is still in its infancy: the realm of regenerative medicine and tissue engineering. Methods: A literature review was performed using PubMed; peer-reviewed publications were screened for relevance in order to identify key surgical innovations influencing regenerative medicine, with a focus on osseous, cutaneous and soft tissue reconstruction. Results: This review describes recent advances in regenerative medicine, documenting key innovations in osseous, cutaneous and soft tissue regeneration that have brought regenerative medicine to the forefront of the surgical imagination. Conclusion: Surgical innovation in the emerging field of regenerative medicine has the ability to make a major impact on surgery on a daily basis. Paper accepted 9 September 2014 Published online in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9672

‘The abdomen, the chest and the brain will forever be shut from the intrusion of the wise and humane surgeon.’ Sir John Ericksen, Surgeon Extraordinaire to Queen Victoria, 1873 Sir John Ericksen has been proven time and time again to be incorrect in his early surgical prediction. Surgery, as one of the oldest and most respected fields, has been built upon continuous innovation. Throughout history, surgeons have been prolific innovators, commencing with the introduction of anaesthesia and antisepsis, which started the transformation of the practice of surgery from a modest contributor to medical progress to a significant force in medical advancement. The dominance of innovation in surgery is hardly surprising, as most surgeons innovate on a daily basis, tailoring therapies and operations to the intrinsic uniqueness of every patient and their disease. Surgeons currently have in their armamentarium in excess of © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd

2500 different procedures; the focus of recent advances in surgery is less on adding to the sheer number of procedures, but rather to ensure improving success of the available treatments1 . Innovation can be defined as the application of better solutions that meet new requirements, unarticulated needs or existing market needs. This is accomplished through more effective products, processes, services, technologies or ideas that are readily available to markets, governments and society2 . As stated by Peter Drucker, the founder of modern management theory, ‘knowledge has to be improved, challenged and increased constantly or it vanishes’. The relentless pursuit of innovation, in both basic scientific and clinical research, has allowed surgery to develop novel approaches to patient care. In the past two decades, surgical innovation has significantly improved patient outcomes, complication rates and length of hospital stay. This improvement is set to continue as minimally invasive surgical techniques, robotic systems BJS 2015; 102: e41–e55

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and virtual reality training enter mainstream use. Worldwide, the number of robot-assisted procedures increased significantly from 80 000 in 2007 to over 200 000 in 20103 . Minimally invasive surgery allows surgeons to carry out complex procedures with reduced inpatient stay and postoperative morbidity. However, there is one key area that has great potential to change the face of surgical practice and which is still in its infancy: the realm of regenerative medicine and tissue engineering. Regenerative medicine is the process of creating living, functional tissue to repair or replace tissue or organ function lost owing to age, disease, damage or congenital defects. Regenerative medicine has the potential to change the way we regard both congenital and acquired disease. This field holds the promise of regenerating damaged tissues and organs in the body by stimulating previously irreparable organs to heal themselves4 . By understanding how individual cells respond to signals, interact with their environments and organize into tissues, researchers have been able to manipulate these processes to mend damaged tissues or even create new tissues, implementing tissue engineering strategies, an important component of regenerative medicine. This review discusses advances in regenerative medicine and tissue engineering proper, before focusing on key regenerative strategies currently in clinical practice, involving osseous, cutaneous and soft tissues. Developments in chemistry, imaging, computational design, engineering and the importance of close clinical collaboration are becoming increasingly relevant as the field matures5 . Although exciting novel developments are highlighted, one caveat to the present review is that the sheer quantity of publications in the field is staggering and simply cannot be condensed into this work.

between scientists, surgeons and physicians. Stem cells, available as building blocks in tissue engineering, can be broken down into two main categories: human adult and embryonic stem cells. The major difference between these cells pertains to their differentiation potential. Embryonic cells are pluripotent and so can differentiate into all cells, whereas adult stem cells are multipotent and so their differentiation potential is restricted. Adult stem cells have now been discovered in many tissues, including blood vessels, skeletal muscle, skin and adipose tissue4 , and can be implemented in tissue regeneration. The ability to generate induced pluripotent stem cells (iPSCs) is one of the major developments in recent years6 . Somatic cells from human adult fibroblasts can be reprogrammed into a primordial embryonic stem cell-like state, with the capacity to develop into all three germ layers by forcing expression of four classical transcription factors (Oct4, Sox2, Klf4 and c-myc; Yamanaka factors)7 . However, subsequent studies8,9 have also shown the capacity to generate iPSCs using fewer factors. As iPSCs are derived by genetic modifications of mature postnatal somatic cells, these cells are not controversial from an ethical point of view. In particular, there is much interest in patient-derived pluripotent stem cells, which are genetically matched to the individual’s own cells, minimizing the risk of rejection by the immune system (Fig. 1). There are, however, concerns relating to iPSC derivation and obstacles (for example risk of teratoma development) that need to be overcome before translation to clinical practice. Recently, Hou and colleagues10 demonstrated the ability to induce pluripotent stem cells chemically without the need for viral transfection, thus reducing potential tumour induction associated with iPSC derivation. Ongoing research is required before iPSCs can become mainstream in regenerative medicine.

Tissue engineering

Tissue engineering has emerged within regenerative medicine as a field focused on developing tissue and organ surrogates to restore, maintain or improve biological functions. The essential constituents of tissue engineering include scaffolds, cells and biologically active molecules, which can combine to result in functional tissues.

Innovation in stem and progenitor cell therapy As surgery strives to harness the body’s own cells for treatment, innovation has led to advances in stem cell-based therapies over the past decade. This concept, first introduced by bone marrow transplantation, the most commonly performed stem cell therapy, has undergone a transformation owing to synergistic work © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd

Decellularization and the transition to the smart scaffold Scaffolds act as mechanical constructs, while also serving as delivery vehicles for cells and/or morphogens. The goal of a scaffold is to simulate the extracellular matrix (ECM), which serves as an active biological tissue, affecting cellular adhesion, migration, proliferation and differentiation11,12 . Biomaterials used as a scaffold must meet some essential biomechanical criteria, such as biocompatibility, adequate mechanical strength, bioresorbability, and sufficient porosity and transport properties to allow ingrowth of cells, influx of nutrients and elimination of waste products11 . Innovation has paved the way for the transformation of a bioinert scaffold to a smart scaffold, which can interact with cells to direct their biological response and even be www.bjs.co.uk

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The ability to generate induced pluripotent stem cells is one of the major developments in the stem cell arena. There is great interest in patient-derived pluripotent stem cells, which are genetically matched to the patient’s own cells, although some obstacles need to be overcome before true translation to clinical practice. iPS cells, induced pluripotent stem cells. (Reproduced with permission from Nishikawa et al. Nat Rev Mol Cell Biol 2008; 9: 725–729)

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responsive to other cells5 . Scaffold engineering is a truly multidisciplinary and rapidly evolving field. Currently, one of the most interesting areas in scaffold development is the implementation of decellularized scaffolds, which have the potential to overcome the challenges associated with mimicking the native ECM topography. Decellularization involves removal of resident cells and a large proportion of the major histocompatibility complex from a tissue or whole organ by use of optimized protocols that rely on perfusion with detergents13 . The ECM is preserved, complete with the native topographical geometry, anatomical features and perfusable vasculature5 . The decellularized scaffold can then be seeded with cells to repopulate the matrix and ensure a degree of functionality before implantation. Biomimetism is the creative initiation of various specific biological systems gaining inspiration from nature14 . It aims to mimic the natural environment of the ECM, because ECM molecules can provide vital signalling to guide cell function and tissue regeneration15 . Thus, decellularized scaffolds offer an attractive option in a number of applications as they provide macroenvironmental and microenvironmental cues at both compositional and structural levels that are likely to direct cellular phenotype. Decellularized scaffolds have, to date, been used successfully in a variety of reconstructive surgical strategies, including human tracheal13,16,17 , murine renal and equine laryngeal18 regeneration (Fig. 2). One relevant population is paediatric patients with congenital heart defects.

Decellularized allogeneic heart valves, manufactured with simple, time-saving and cost-effective procedures, have recently shown promise as an effective therapeutic alternative to current treatment19 . Although there remain considerable challenges facing the development of the ideal artificial scaffold, increased understanding of the importance of scaffold topography and porosity, degradation rates and incorporation of bioactive molecules has continued abreast of technological advances, as summarized by Harrison et al.5 . Three-dimensional (3D) printing strategies for manufacture have accelerated personalized scaffold development, and it can be envisaged that this technology will allow high-throughput production and increased provision of personalized scaffolds for reconstructive surgery.

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Second-generation growth factors and gene therapy: efforts to avoid the supraphysiological A growth factor (GF) may be incorporated into a construct in a number of ways: by soaking the scaffold in a solution of GF for fast release, by incorporation into scaffolds, or by covalent immobilization for controlled and extended release. Conversely, GFs may be incorporated into seeded cells via molecular and genetic modification20 . The release of GFs added to scaffolds is usually by passive diffusion or coupled to the rate of biomaterial degradation20 . GFs covalently linked to scaffolds may be released according to BJS 2015; 102: e41–e55

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Cells and matrix construct Air Culture medium

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Fig. 2 Bioreactor developed for airway tissue engineering (engineered trachea). a Schematic lateral view, highlighting the rotation of the matrix around its longitudinal axis. The device has separate compartments for lumen and outer surface, and is rotated regularly through a motor to apply the sheer stress needed for growth, distribution of nutrients and waste, and to ensure even exposure to applied cells. b Sealed device. c Bioreactor with graft in situ. d Bioreactor after removal of graft. e Final graft immediately before surgical implantation. (Reproduced with permission from Macchiarini et al.17 )

cellular demands, in a more closely controlled method21 . Ehrbar and co-workers22 demonstrated that controlled vascular endothelial growth factor (VEGF) release from scaffold leads to a more organized vasculature in comparison with the vasculature that arises from uncontrolled VEGF release. Despite isolation and molecular cloning of GFs, tissue engineering in the clinical context is challenged by supraphysiological doses of human recombinant morphogens and the associated expense required to yield adequate clinical effects. However, the development of second-generation recombinant GFs is an exciting area in tissue engineering. Current novel goals for GF development include incorporation of the following characteristics: improved binding affinity to specific target cell surface GF receptors, decreased sensitivity to natural GF inhibitors, better immunogenicity profile, and increased solubility and stability23 . Gene therapy has been explored as an alternative to recombinant GF therapy. A more cost-effective method of GF delivery is the incorporation of genetically modified cells, such as VEGF-releasing adipose-derived stem cells (ASCs) or cells manipulated to release GFs20,24 – 26 . Gene therapies with regulated expression systems may provide substantial improvement in efficacy and safety compared with protein-based therapies. Synthetic gene switches,

activated by drugs, or light or heat stimuli, provide several avenues for non-invasive regulation of the expression of GF transgenes. Through new gene therapy platforms such as these, active control over GF signalling can be achieved to accelerate tissue regeneration27 . With this approach, it is possible to achieve sustained GF expression at regeneration sites and, in many cases, tissue regeneration that is superior to that achieved with recombinant proteins28 .

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Harnessing the intrinsic capacity of bone to regenerate Distraction osteogenesis (DO), a technique championed by Gavril Ilizarov29 , simultaneously increases bone length and the volume of surrounding tissues. Bone is one of the few tissues in the human body that possess intrinsic capacity to heal spontaneously following injury. DO is a surgical technique in which the intrinsic capacity of bone to regenerate is harnessed to lengthen bone or to replace large segments of bone. DO is considered an example of in vivo bone tissue engineering. It is superior to other methods of bone regeneration in the management of bone loss, because this technique allows the spontaneous formation of new native bone without the need for a bone graft30 . Initially described for use in long bones of the limbs, its scope has extended to include the craniofacial skeleton31 – 33 . BJS 2015; 102: e41–e55

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Distraction osteogenesis There are six key stages in DO, which include preoperative planning, operative, latency, distraction, consolidation and retention phases. The area in which development and innovation has clearly influenced daily surgical practice is virtual surgical planning. Computer-aided design and computer-aided manufacturing, also known as 3D printing, have revolutionized osseous reconstructive surgery. Rapid prototyping technology, together with widespread availability of high-resolution medical imaging, has allowed the generation of contoured 3D models that provide visual and tactile information for optimization of preoperative planning. The use of 3D CT images in virtual surgical planning was first reported by Cutting and colleagues34 , and these principles have since been expanded to facilitate development of personalized 3D models that allow surgeons to rehearse their surgical strategy and distraction plan. In the past, this would have been done on the operating table, prolonging surgery and anaesthesia. Using these models, one can map out the surgery, cut by cut, and commission printed surgical jigs, or cutting templates, that offer a road map in the operating theatre35,36 . Increased understanding of the biological processes resulting in bone regenerate formation has led to efforts to optimize additional phases of DO. For instance, efforts are under way to identify the best method of surgical osteotomy. Richards and co-workers37 witnessed greater bone regeneration in a rabbit tibial model when the distraction followed an osteotomy of 30∘ compared with one vertical to the bone. This suggests that an increase in shear forces may provide greater stimulation of osteoblasts and ossification centres37 . In addition, novel technologies are also being implemented to assess their impact on DO. For instance, Taub and Collins38 reported the use of a piezoelectric saw for DO in the paediatric mandible, hypothesizing that intermittent ultrasonic vibrations used to perform the osteotomy would minimize the risk of injury to adjacent soft tissue, particularly the inferior alveolar nerve. The addition of morphogens, cells and scaffolds has also been explored, each offering therapeutic advantages to standard procedures. Addition of GFs, including fibroblast growth factor 2 and bone morphogenetic protein (BMP) 2, can accelerate bone regeneration in animal models39 . So too, injection of ASCs into the distracted callus has been shown to increase the bone density of osseous regenerate significantly compared with control. This is thought to be secondary to both accelerated osteogenic differentiation and secretion of humoral factors such as BMP-2 and VEGF that can promote osteogenesis or © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd

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angiogenesis40,41 . Interestingly, Sun et al.42 reported that gene therapy using Runt-related gene 2 (a master switch regulating the number of genes involved in osteoblast activation)-modified ASCs promoted new bone formation during osteoporotic mandibular DO42 . DO has been augmented with autologous bone marrow aspirate and platelet-reduced plasma injection at the osteotomy site, with a notable increase in the rate of cortical bone healing43 . Finally, scaffold design is evolving rapidly, and has implications for bone regeneration and DO. Bioabsorbable scaffold-based cellular delivery has been shown to accelerate regeneration and quality of bone regenerate in porcine DO44 . Further innovations in scaffold, cell and GF-augmented DO hope to challenge the main concern: the pace and adequacy of bone regeneration.

Innovative device design in distraction osteogenesis Turning to device innovation, as DO is now being performed more readily, surgeons have begun to investigate ways to refine the procedure. In the craniofacial and axial skeleton, one of the biggest disadvantages of DO is the requirement for device removal. The use of resorbable distractors eliminates the need for a second procedure (Fig. 3). An example of a resorbable distractor is Lactosorb® (Biomet, Jacksonville, Florida, USA), composed of a co-polymer comprising 82 per cent poly L-lactide and 18 per cent polyglycolic acid, which maintains strength for 3–4 months and is fully resorbed by 12 months45,46 . This allows retention of strength during the crucial period of consolidation, while obviating the need and associated risks of a second procedure. These distractors have been used in monobloc, mid-facial, mandibular and posterior cranial distraction46 – 48 . In addition to the immediate risks, there is increasing awareness of the potential deleterious effect of multiple general anaesthetics on cognitive development in children49 , which is an important issue when considering surgical correction of craniosynostosis in a population already prone to developmental issues. During the distraction period, the device must be activated manually to create callus elongation, resulting in prolonged hospitalization and multiple outpatient visits. This has potential risk for human error, especially on repeated applications. Recently, Aykan and co-workers50 reported a successful study detailing an electromechanical distractor used for sheep mandibular DO, with an automated distraction phase lasting a total of 20 days (Fig. 3). If shown to be successful in ongoing human studies, electromechanical distraction may have the potential to replace manual distraction, allowing high-resolution movement capacity and improved patient comfort. www.bjs.co.uk

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Skin regeneration

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Surgical disciplines are confronted with cutaneous wounds on a daily basis. The mechanisms that govern skin healing and the elusive goal of scarless wound healing are, therefore, a natural focus of surgical innovation. The biological mechanisms underlying skin repair after injury are among the most complex processes occurring in multicellular organisms51 . In humans, fibrotic scar formation is the typical response to injury, and provides early restoration of tissue integrity rather than functional repair52 . Manipulating the body’s response to cutaneous injury, to direct it away from the simple disposition of an acellular mass of epithelialized ECM towards true regenerative healing, has been a longstanding goal of surgical research. Recent advances have resulted in innovative therapeutics such as mechanomodulatory treatments and biomimetic scaffolds with, and without cellular components.

Mechanomodulatory therapy for scarless wound healing

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Examples of innovative devices for use in distraction osteogenesis. a L-shaped device being applied to mandible. The neck between the drive screw and fixation holes allows thermal contouring to non-linear mandibular shapes. b Resorbable distractors from infant (top) to paediatric (bottom). c Electronic component of the electromechanical distractor in situ in a sheep model of distraction osteogenesis. (a,b Reproduced with permission from Burstein45 ; c reproduced with permission from Aykan et al.50 )

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The connection between mechanical forces and cutaneous fibrosis was first established more than 150 years ago53 ; however, it is only recently that the molecular mechanisms underlying mechanocutaneous connection have been elucidated. Cutaneous wound healing is a process involving a complex cascade of biochemical and cellular events in overlapping phases: haemostasis, inflammation, proliferation and eventually remodelling, with scar formation52,54 . Today it is known that all phases of wound healing are influenced by mechanical forces55 , and promising therapies seeking to promote regeneration based on these advances are currently in development. Mechanical forces play a significant role in scar development56,57 ; compression dressings58 – 62 , and even paper tape63 , have demonstrated some efficacy in scar reduction. A more promising approach to alleviation of scar formation and increasing the body’s own regenerative capacity in the setting of cutaneous injury is to modulate environmental cues by mechanical offloading. Active mechanical offloading (as opposed to passive tissue approximation) has been effective in both preclinical and clinical trials, reducing fibrosis by influencing numerous mechanoresponsive signalling pathways64,65 . Both a phase I clinical trial65 and a multicentre randomized clinical trial66 have demonstrated that stress-shielding of surgical incisions leads to significant improvements in scar appearance. These findings suggest that a mechanomodulatory approach addresses the multiple pathways involved in scar development, leading to a less fibrotic and more regenerative response (Fig. 4). www.bjs.co.uk

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Improving cutaneous scar formation by controlling the mechanical environment: large animal and phase I studies. Stress shielding significantly reduces scar formation in human surgical incisions. a Abdominoplasty procedures involve the excision of an extensive amount of soft tissue (full-thickness skin and subcutaneous fat), which results in a high-tension (red arrows) incisional wound after closure with sutures. It is hypothesized that these forces predispose wounds to hypertrophic scar formation and that offloading of mechanical stresses within abdominal incisions with a dynamic stress-shielding polymer will reduce scar formation. b Photographs of paired within-patient abdominal incisions at 6–12 months after surgery (paired rows). Note the scar widening, elevation, irregularity and discoloration in unshielded control incisions (left columns) compared with stress-shielded incisions (right columns). Scale bar 1 cm. c Evaluation of professional photographs by both a lay panel and an expert panel demonstrated a significant improvement in scar appearance based on standardized scoring on a visual analogue scale (VAS); values are mean(s.e.m.). *P < 0⋅010. (Reproduced with permission from Gurtner et al.65 ) Fig. 4

Alternatively, a number of pharmacological targets have shown promise for the reduction of mechanically induced scarring, with the array of targets including constituents of the hedgehog67 and canonical Wnt68 pathways, modulators of transforming growth factor β signalling69 , heat-shock protein 9070 and interleukin 10, which modulates fibrosis via numerous signalling pathways71 – 76 . Although progress has been made in the experimental © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd

setting, clinical application of pharmacological antiscarring therapies remains elusive.

Innovative scaffolds for skin regeneration Biomimetic scaffolds are next-generation dressings that establish a functional cell niche in addition to providing wound coverage, leading to enhanced skin healing. www.bjs.co.uk

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Bioactive dressings are typically engineered from components naturally present in the ECM or composed of polymers constructed to mimic it77 . For example, biomimetic collagen hydrogels have been shown to accelerate early wound healing by modifying cell recruitment and augmenting granulation tissue formation78 . Biological matrices have evolved recently from being simple ECM replacements for deep or full-thickness wounds to drug and cell delivery vehicles. Novel regenerative matrices are capable of both encouraging engraftment and proliferation of endogenous cells, and enhancing the functionality of cell-based therapeutics79 . Pullulan (a polysaccharide polymer)–collagen matrices seeded with mesenchymal stem cells (MSCs) enhance cell survival and engraftment in a high-oxidative-stress environment by quenching free radicals80 . MSCs delivered in such a structured matrix environment have demonstrated enhanced efficacy by increased angiogenic cytokine expression, leading to augmented neovascularization in cutaneous wounds81 . The efficiency of topical progenitor cell therapy can be improved by novel approaches to scaffold seeding. Employing an innovative seeding approach based on capillary force, ASCs could be seeded more rapidly and gently compared with established methods (Fig. 5), making this approach fit for clinical translation. Capillary force-seeded ASCs displayed a significantly enhanced regenerative protein expression profile (Fig. 5), which resulted in enhanced cutaneous wound healing and vascularity82 . In addition to improving wound healing and skin regeneration by increased neovascularization, scaffold-seeded progenitor cells also enhance tissue repair by immune modulation. MSCs promote scarless wound healing by paracrine modulation of leucocyte activity, and by directly secreting antifibrotic cytokines and GFs83 . However, mode of delivery can affect the immunomodulatory effects of MSCs and their impact on scar formation. ASCs delivered to cutaneous excisional wounds via an ECM patch attenuate wound fibrosis more effectively than ASCs applied without scaffold support84 .

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Despite significant scientific advances and early clinical trials, clinical translation of progenitor cell-seeded biomimetic scaffolds for skin regeneration remains a challenge. However, innovative therapies based on emerging concepts arising from the intersection of engineering, molecular signalling and stem cell biology will potentially result in the transformation of fibrotic healing into skin regeneration. Looking forward, work to understand the genetic and epigenetic indicators that might predispose to excessive scarring or successful regenerative therapy may enhance skin tissue engineering further.

Autologous fat transfer and soft tissue reconstruction Adipose tissue is an optimal, autogenous soft tissue filler material that is abundant in the body; autologous fat transfer has evolved as an essential tool in regenerative medicine85 . However, at every stage from harvesting, to processing, to grafting, a marked degree of uncertainty and disagreement still remains with regard to this capricious technique86,87 . In the era of evidence-based medicine, emphasis is now being placed on comprehending the scientific basis of fat transfer. Lipoaspiration was first developed by Dr Yves-Gerard Illouz as a cosmetic surgical technique to remove fat from the human body, discarding the fat as medical waste, with little respect for the viability of the constituents of adipose tissue88 . If the fat removed is to be transferred to another site, then preservation of fat viability becomes important86 .

Optimizing fat procurement and subsequent transfer When fat transfer became incorporated into tissue engineering strategies, there were questions regarding fat procurement and subsequent handling. Several issues were noted early on, which included unpredictability and a low survival rate owing to partial necrosis. Importantly, ASCs

Fig. 5 Biomimetic pullulan–collagen hydrogels can be engrafted with adipose-derived stem cells (ASCs) by a novel capillary force-driven seeding technique. a Cells are actively engrafted into a 5 per cent collagen–pullulan hydrogel via a combination of hydrophobic, entropic and capillary forces, the last a function of hydrogel pore width and liquid properties of the ASC solution. h, Height; θ, contact angle; γ, surface tension; ρ, liquid density; r, pore radius; g, gravitational force. b Capillary seeding demonstrated superior efficacy compared with centrifugal, injection and orbital seeding approaches. c Immunocytochemistry reveals increased expression of Oct4 protein (a marker for undifferentiated cells, shown in red) in hydrogel-seeded ASCs compared with plated ASCs. Of note, the ASCs are shown in green as they were derived from a green fluorescent protein-labelled mouse. Nuclei are stained blue (4′ ,6-diamidino-2-phenylindole). Scale bar 100 μm. d Flow cytometric analysis demonstrates increased levels of stemness and mesenchymal stem cell markers in hydrogel-seeded ASCs. The left panel shows representative histograms, with shaded peaks representing the negative control. The right panel shows the mean(s.e.m.) percentage expression of each marker. ALP, alkaline phosphatase. *P < 0⋅050. (Adapted with permission from Garg et al.82 )

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Innovations in autologous fat transfer for soft tissue reconstruction. a Adipose Tissue Injector with 60-ml syringe and 2-mm grafting cannula attached. Depressing a button on the tail end of the device (not shown) allows the user to switch between a slow and fast mode. The yellow trigger may be pressed once to deliver a set volume of fat or held down for continuous delivery of fat aliquots. b Haematoxylin and eosin staining of fat processed with the traditional (modified Coleman) technique; note marked injury to the fat shown by the presence of large vacuoles (*), fibrosis (arrowhead) and inflammatory infiltrate (arrow). c Haematoxylin and eosin staining of fat processed with the Adipose Tissue Injector; note the significantly improved integrity and architecture of fat cells. d BRAVA® applied to patient with tuberous breasts. e MRI illustrating breasts after applying the BRAVA® bilaterally for 3 weeks; note the

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markedly increased vascularity and size of the parenchyma (lower panel) compared with baseline MRI (upper panel). f Computergenerated optimal lipoaspirate transplantation pathway to distribute fat evenly, developed using a predictive algorithm that integrates a three-dimensional model of the patient’s chest. (a–c Reproduced with permission from Chung et al.97 ; d reproduced with permission from Khouri et al. Plast Reconstr Surg 2014; 133: 796–807; e reproduced with permission from Khouri et al. Plast Reconstr Surg 2012; 129: 1173–1187; f reproduced with permission from Patete and Baroni100 )

found in adipose tissue are thought to increase the survival of fat graft, and Chung et al.89 illustrated that different methods of lipoaspiration yielded ASCs of variable quality. Although recent studies suggest that ASCs harvested by suction-assisted liposuction and ultrasound-assisted liposuction may have equivalent adipogenic and osteogenic differential potential (D. Duscher, D. Atashroo, G. C. Gurtner and M. T. Longaker, unpublished data), laser-assisted liposuction impedes the ability of these cells to differentiate towards the adipogenic and osteogenic lineages89 . In an effort to define the optimal method of fat procurement,

recent research has revolved around the pressure used during lipoaspiration. Lee and colleagues90 did not find any significant difference in graft weight or histology when examining fat procured under higher aspiration pressures, whereas a more recent study91 reported that low harvest pressure enhanced autologous fat graft viability. Aside from the harvest technique, variability in injection has also contributed to inconsistent outcomes for fat grafting. Lee and colleagues90 also noted that injecting at a low flow rate (with low shear conditions) protects the fat, improving its survival and quality compared with faster

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injection rates. Recent studies in the authors’ laboratory suggest that there are indeed optimal cannula sizes and flow rates that translate into significantly improved integrity of grafted lipoaspirate (T. Wearda, D. Atashroo, D. C. Wan and M. T. Longaker, unpublished data). With regard to cell-based enhancement of fat grafts, Yoshimura’s group92,93 introduced the concept of cell-assisted lipotransfer, which combines fat with supernormal levels of ASCs. Using this enrichment technique, they concluded that this innovation resulted in enhanced graft survival, hypothesizing that the improved survival outcome was secondary to ASC differentiation into vascular endothelial cells and subsequent contribution to neoangiogenesis in the acute phase of transplantation. Adding to this hypothesis, a Danish randomized trial94 reported that ASC graft enrichment led to significantly higher rates of graft survival in comparison with control fat grafts. Many have questioned whether there is an optimal ratio of ASC enrichment to fat graft volume. Murine studies have suggested that precise mixing of a defined concentration of ASCs with lipoaspirate may provide optimal fat graft survival (K. Paik, M. T. Chung, M. T. Longaker and D. C. Wan, unpublished data).

Innovative devices in soft tissue reconstruction Many early reports of fat grafting revolved around small-volume transfer, particularly for reconstruction of soft tissue deficits in the craniofacial region. More recently, Khouri and colleagues introduced an innovative device (BRAVA® Breast Enhancement and Shaping System; BRAVA, Coconut Grove, Florida, USA) for large-volume soft tissue reconstruction. Studies95,96 have suggested that using negative pressure to pretreat recipient sites allows more compliance, facilitating larger-volume fat grafts (Fig. 6). Alternative devices have also been developed, including the Adipose Tissue Injector (ATI) (TauTona Group, Menlo Park, California, USA) to facilitate both large- and small-volume delivery in a reproducible manner97 (Fig. 6). By controlling the flow rate and minimizing syringe exchange, the ATI curtailed deleterious effects of shear stress and preserved fat integrity, resulting in improved graft survival and quality97,98 . A few other notable device innovations have also been introduced to this popular field. Khouri and colleagues99 introduced the LipoGrafter™ (Lipocosm, Key Biscayne, Florida, USA), a hand suction device that implements a syringe vacuum source, enabling constant pressure. Finally, Patete and Baroni100 described a lipotransfer device that controls injection flow rate by using infrared optical motion tracking to assess syringe withdrawal speed in real time (Fig. 6). © 2015 BJS Society Ltd Published by John Wiley & Sons Ltd

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Discussion

The relentless pursuit of innovation in both basic science and clinical research has allowed surgery to develop novel approaches to patient care. Innovation continues to influence tissue regeneration of the surgical patient, and the translation of novel technologies from the bench to the bedside has only just begun. The advancement of tissue engineering in surgical practice requires a sound understanding of complex processes affecting tissue repair and regeneration. Although it is challenging to mimic nature, by developing an understanding of tissue regenerative pathways in the laboratory, surgical patients receive better care and innovative novel methodologies can be used to affect patient care. The three pillars of regenerative medicine and tissue engineering proper include scaffolds, cells and GFs. Understanding how to manipulate and best use these pillars are small steps towards the elusive goal: whole-organ tissue engineering. Acknowledgements

R.T. and D.A. contributed equally to this article. The authors acknowledge the following ongoing support for this work: National Institutes of Health (R01DE02183, R21DE02423001, R01DE019434 and U01HL099776 to M.T.L., R01-DK074095, R01-EB005718 and R01-AG025016 to G.C.G.), the Oak Foundation, the Hagey Laboratory for Pediatric Regenerative Medicine, the American College of Surgeons Franklin H. Martin Faculty Research Fellowship (to D.C.W.), the Stanford University Child Health Research Institute Faculty Scholar Award (to D.C.W.), the Plastic Surgery Foundation/Plastic Surgery Research Council Pilot Grant (to R.T. and D.A.), and the Stanford University Transplant and Tissue Engineering Center of Excellence Fellowship (to R.T. and A.M.). M.T.L. and G.C.G. are founders, have equity in and serve on the Board of Directors of the TauTona Group and Neodyne Biosciences. D.C.W. is a consultant for Neodyne Biosciences. Disclosure: The authors declare no other conflict of interest. References 1 Gawande A. Two hundred years of surgery. N Engl J Med 2012; 366: 1716–1723. 2 Hultman CS, Friedstat JS. The ACAPS and SESPRS surveys to identify the most influential innovators and innovations in plastic surgery: no line on the horizon. Ann Plast Surg 2014; 72: S202–S207. 3 Barbash GI, Glied SA. New technology and health care costs – the case of robot-assisted surgery. N Engl J Med 2010; 363: 701–704.

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