Comment
The ready availability of tissues or organs to replace or repair those diseased or damaged is a ubiquitous clinical need, and the rapidly developing field of tissue engineering might offer innovative solutions. Two Articles1,2 in The Lancet show the incremental expansion of the applications of tissue-engineering technology to reconstructive surgery. Application of cells to a scaffold, with or without added chemical or mechanical stimuli, followed by their use for repairing congenital or acquired defects was well established in the 1990s3 and has led notably to the treatment for congenital bladder defects clinically available in the USA. Following on well documented successes in the clinical application of tissueengineered skin,4 blood vessels,5 urethra,6 and bladder wall,7 investigators used similar principles of seeding autologous differentiated cells onto collagen scaffolds to treat patients with nasal defects2 after cancer resection, or seeding onto extracellular-matrix-derived scaffolds to treat patients with vaginal aplasia.1 In four girls aged 13–18 years, with a rare form of vaginal aplasia, Atlántida Raya-Rivera’s team in Mexico joined the Wake Forest team to create customised three-dimensional vaginal replacements with decellularised porcine intestinal submucosal scaffolds.1 In this pilot cohort study, they cultured, expanded, and seeded epithelial and muscle cells onto biodegradable scaffolds. After the constructed organs had matured in an incubator, these were implanted with a perineal approach. The investigators recorded the patients’ history and undertook physical examinations, vaginoscopy, serial tissue biopsy samples, MRIs, and self-administered Female Sexual Function Index questionnaires. At a mean follow-up of 81 months, self-administered Female Sexual Function Index questionnaires revealed excellent functional results and quality of life. Vaginal growth as the girls grew was evident, and annual biopsy samples showed normal vaginal wall. In an observational first-in-human trial in Switzerland and the UK, Ilario Fulco and colleagues2 used nasal septal cartilage cells seeded onto porcine collagen scaffolds to implant intra-operatively shaped engineered cartilage grafts under pedicled facial skin flaps (paramedian forehead or nasolabial flaps). The investigators report
restoration of contour and nasal airflow to the noses of two women and three men, aged 76–88 years, undergoing substantial resections of external nasal tissue as treatment for skin cancer. After flap refinement at 6 months, Fulco and colleagues2 took biopsy samples of repair tissues and histologically analysed them. Safety and feasibility of the procedure 12 months after reconstruction were the primary outcomes. Importantly, the staged reconstruction in the patients permitted histological assessment of the implanted tissue and confirmed sustained restoration of all three layers of the nose that had been reconstructed. At 12 months, no adverse events had been recorded and patients were satisfied with the aesthetic and functional outcomes. Together, these two studies1,2 begin to answer three of the key scientific questions posed to, and by, the translational tissue-engineering community.8 First, are biological scaffolds, with or without cells, replaced by scar tissue or native quality tissue over time? In both studies, findings show excellent evidence of multilayer remodelling in a manner consistent with the normal tissues restored. Second, can tissue-engineered organs grow if implanted in children and adolescents? Raya-Rivera’s group1 has provided the first, tentative evidence that engineered organs and tissues can indeed be responsive to the growth needs of children. Third, and possibly most importantly, is it possible to scale up the volume of organs and tissue replaced using tissue-engineering technologies? The size of patches successfully replaced in paediatric bladder7 and urethra6 with tissue-engineered products, for example, is very small compared with the vaginal vaults implanted by Raya-Rivera and colleagues,1 even before growth occurred. In the study by Raya-Rivera and colleagues,1 tissue integrity was maintained despite the fact that survival still depended on local angiogenesis, through mechanisms still to be fully understood. Some have doubted that the short-term and longterm physiological needs of implanted cells and their successors would be met by in-situ angiogenesis as opposed to the alternatives of prevascularisation or transfer with vascular pedicles,8 methods presently used with conventional organ transplants or free flap reconstruction.9 The finding that in-situ angiogenesis might be adequate for even large areas of tissue
www.thelancet.com Published online April 11, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60533-X
Corbis
Tissue engineering’s green shoots of disruptive innovation
Published Online April 11, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60533-X See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(14)60544-4 and http://dx.doi.org/10.1016/ S0140-6736(14)60542-0
1
Comment
replacement starts to edge tissue engineering towards the mainstream of organ and tissue replacement needs. Of course, progression from first-in-human experiences in only a few patients, such as those reported by Raya-Rivera and Fulco and their colleagues, to a full integration into health systems involves many steps, and is often an uphill struggle. There is a need for larger trials, with efficacy shown in larger patient cohorts with longterm follow-up; meanwhile, clinical grade processing, scale-out, and commercialisation all incur substantial time and cost. However, these barriers are not unique to tissue engineering, and many countries now have large translational income streams, engaged biotech companies, and streamlined regulatory processes that might lower these barriers. Clay Christensen10 has suggested that most changes in any market, possibly especially health care, evolve and improve existing technologies and modus operandi—for example, MRI scanners continue to improve generationally. These changes, which improve the patient’s experience and accuracy of diagnosis, are sustaining innovations: they improve an existing system that is understood by patients and that supports specialised industry, doctors, and health-care systems. By contrast, tissue engineering, and the various shades of regenerative and cellular therapies it partners, is a disruptive technology.11 The first forays into the clinic, as with gene therapy, for example, serve niche populations at high individual cost. At the same time, early phase experiences such as those reported in The Lancet both answer and pose the questions necessary for tissue engineering’s own incremental improvement. With these early findings of scaling up in volume, growth with age, and intrinsic angiogenesis at scale, the tissue engineering innovation curve is now arcing upwards: those issues that might limit penetration of the mainstream healthcare processes of organ and tissue replacement now have incremental scientific solutions. Equally important is the need to reduce costs of tissue-engineered solutions such that they might start to challenge conventional technologies within 10–20 years (eg, development of customised nanotechnological, 3D-printed scaffolds).12 For the first time, scientists, doctors, and the health-care industry can see how extrapolation of this curve could one day meet demands of mainstream patients.
2
Early automobile technology, although highly innovative, was the preserve of those who could afford it for many years. It was only when Henry Ford’s mass production brought automobiles to everyone’s street, in numbers yet at affordable cost, that the industry of the horse-drawn carriage passed away. These two Lancet studies show that those who practise conventional tissue reconstruction and organ transplantation, and the health-care and commercial industries which support them, should finally be taking the quirky minnows of tissue engineering quite seriously. Disruptive innovation might be nigh. *Martin A Birchall, Alexander M Seifalian UCL Ear Institute, Royal National Throat Nose and Ear Hospital, London WC1X 8DA, UK (MAB); Nanotechnology and Regenerative Medicine, Division of Surgery and Interventional Science, University College London, Royal Free London NHS Foundation Trust Hospital, London, UK (AMS) [email protected] We declare that we have no competing interests. 1
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Raya-Rivera AM, Esquiliano D, Fierro-Pastran R, et al. Tissue-engineered autologous vaginal organs in patients: a pilot cohort study. Lancet 2014; published online April 11. http://dx.doi.org/10.1016/S01406736(14)60542-0. Fulco I, Miot S, Haug MD, et al. Engineered autologous cartilage tissue for nasal reconstruction after tumour resection: an observational first-inhuman trial. Lancet 2014; published online April 11. http://dx.doi. org/10.1016/S0140-6736(14)60544-4. Badylak SF, Taylor D, Uygun K. Whole-organ tissue engineering: decellularization and recellularization of three-dimensional matrix scaffolds. Annu Rev Biomed Eng 2011; 13: 27–53. Centanni JM, Straseski JA, Wicks A, et al. StrataGraft skin substitute is well-tolerated and is not acutely immunogenic in patients with traumatic wounds: results from a prospective, randomized, controlled dose escalation trial. Ann Surg 2011; 253: 672–83. Olausson M, Patil PB, Kuna VK, et al. Transplantation of an allogeneic vein bioengineered with autologous stem cells: a proof-of-concept study. Lancet 2012; 380: 230–37. Bhargava S, Patterson JM, Inman RD, MacNeil S, Chapple CR. Tissue-engineered buccal mucosa urethroplasty-clinical outcomes. Eur Urol 2008; 53: 1263–69. Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet 2006; 367: 1241–46. Delaere PR, Hermans R. Clinical transplantation of a tissue-engineered airway. Lancet 2009; 373: 717–18. Jabir S, Frew Q, El-Muttardi N, Dziewulski P. A systematic review of the applications of free tissue transfer in burns. Burns 2014; published online Feb 8. DOI:10.1016/j.burns.2014.01.008. Christensen CM, Bohmer R, Kenagy J. Will disruptive innovations cure health care? Harv Bus Rev 2000; 78: 102–12. Christensen CM. The innovator’s solution: creating and sustaining successful growth. Boston, MA: Harvard Business Press, 2003. de Mel A, Seifalian AM, Birchall MA. Orchestrating cell/material interactions for tissue engineering of surgical implants. Macromol Biosci 2012; 12: 1010–21.
www.thelancet.com Published online April 11, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60533-X
The ready availability of tissues or organs to replace or repair those diseased or damaged is a ubiquitous clinical need, and the rapidly developing field of tissue engineering might offer innovative solutions. Two Articles1,2 in The Lancet show the incremental expansion of the applications of tissue-engineering technology to reconstructive surgery. Application of cells to a scaffold, with or without added chemical or mechanical stimuli, followed by their use for repairing congenital or acquired defects was well established in the 1990s3 and has led notably to the treatment for congenital bladder defects clinically available in the USA. Following on well documented successes in the clinical application of tissueengineered skin,4 blood vessels,5 urethra,6 and bladder wall,7 investigators used similar principles of seeding autologous differentiated cells onto collagen scaffolds to treat patients with nasal defects2 after cancer resection, or seeding onto extracellular-matrix-derived scaffolds to treat patients with vaginal aplasia.1 In four girls aged 13–18 years, with a rare form of vaginal aplasia, Atlántida Raya-Rivera’s team in Mexico joined the Wake Forest team to create customised three-dimensional vaginal replacements with decellularised porcine intestinal submucosal scaffolds.1 In this pilot cohort study, they cultured, expanded, and seeded epithelial and muscle cells onto biodegradable scaffolds. After the constructed organs had matured in an incubator, these were implanted with a perineal approach. The investigators recorded the patients’ history and undertook physical examinations, vaginoscopy, serial tissue biopsy samples, MRIs, and self-administered Female Sexual Function Index questionnaires. At a mean follow-up of 81 months, self-administered Female Sexual Function Index questionnaires revealed excellent functional results and quality of life. Vaginal growth as the girls grew was evident, and annual biopsy samples showed normal vaginal wall. In an observational first-in-human trial in Switzerland and the UK, Ilario Fulco and colleagues2 used nasal septal cartilage cells seeded onto porcine collagen scaffolds to implant intra-operatively shaped engineered cartilage grafts under pedicled facial skin flaps (paramedian forehead or nasolabial flaps). The investigators report
restoration of contour and nasal airflow to the noses of two women and three men, aged 76–88 years, undergoing substantial resections of external nasal tissue as treatment for skin cancer. After flap refinement at 6 months, Fulco and colleagues2 took biopsy samples of repair tissues and histologically analysed them. Safety and feasibility of the procedure 12 months after reconstruction were the primary outcomes. Importantly, the staged reconstruction in the patients permitted histological assessment of the implanted tissue and confirmed sustained restoration of all three layers of the nose that had been reconstructed. At 12 months, no adverse events had been recorded and patients were satisfied with the aesthetic and functional outcomes. Together, these two studies1,2 begin to answer three of the key scientific questions posed to, and by, the translational tissue-engineering community.8 First, are biological scaffolds, with or without cells, replaced by scar tissue or native quality tissue over time? In both studies, findings show excellent evidence of multilayer remodelling in a manner consistent with the normal tissues restored. Second, can tissue-engineered organs grow if implanted in children and adolescents? Raya-Rivera’s group1 has provided the first, tentative evidence that engineered organs and tissues can indeed be responsive to the growth needs of children. Third, and possibly most importantly, is it possible to scale up the volume of organs and tissue replaced using tissue-engineering technologies? The size of patches successfully replaced in paediatric bladder7 and urethra6 with tissue-engineered products, for example, is very small compared with the vaginal vaults implanted by Raya-Rivera and colleagues,1 even before growth occurred. In the study by Raya-Rivera and colleagues,1 tissue integrity was maintained despite the fact that survival still depended on local angiogenesis, through mechanisms still to be fully understood. Some have doubted that the short-term and longterm physiological needs of implanted cells and their successors would be met by in-situ angiogenesis as opposed to the alternatives of prevascularisation or transfer with vascular pedicles,8 methods presently used with conventional organ transplants or free flap reconstruction.9 The finding that in-situ angiogenesis might be adequate for even large areas of tissue
www.thelancet.com Published online April 11, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60533-X
Corbis
Tissue engineering’s green shoots of disruptive innovation
Published Online April 11, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60533-X See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(14)60544-4 and http://dx.doi.org/10.1016/ S0140-6736(14)60542-0
1
Comment
replacement starts to edge tissue engineering towards the mainstream of organ and tissue replacement needs. Of course, progression from first-in-human experiences in only a few patients, such as those reported by Raya-Rivera and Fulco and their colleagues, to a full integration into health systems involves many steps, and is often an uphill struggle. There is a need for larger trials, with efficacy shown in larger patient cohorts with longterm follow-up; meanwhile, clinical grade processing, scale-out, and commercialisation all incur substantial time and cost. However, these barriers are not unique to tissue engineering, and many countries now have large translational income streams, engaged biotech companies, and streamlined regulatory processes that might lower these barriers. Clay Christensen10 has suggested that most changes in any market, possibly especially health care, evolve and improve existing technologies and modus operandi—for example, MRI scanners continue to improve generationally. These changes, which improve the patient’s experience and accuracy of diagnosis, are sustaining innovations: they improve an existing system that is understood by patients and that supports specialised industry, doctors, and health-care systems. By contrast, tissue engineering, and the various shades of regenerative and cellular therapies it partners, is a disruptive technology.11 The first forays into the clinic, as with gene therapy, for example, serve niche populations at high individual cost. At the same time, early phase experiences such as those reported in The Lancet both answer and pose the questions necessary for tissue engineering’s own incremental improvement. With these early findings of scaling up in volume, growth with age, and intrinsic angiogenesis at scale, the tissue engineering innovation curve is now arcing upwards: those issues that might limit penetration of the mainstream healthcare processes of organ and tissue replacement now have incremental scientific solutions. Equally important is the need to reduce costs of tissue-engineered solutions such that they might start to challenge conventional technologies within 10–20 years (eg, development of customised nanotechnological, 3D-printed scaffolds).12 For the first time, scientists, doctors, and the health-care industry can see how extrapolation of this curve could one day meet demands of mainstream patients.
2
Early automobile technology, although highly innovative, was the preserve of those who could afford it for many years. It was only when Henry Ford’s mass production brought automobiles to everyone’s street, in numbers yet at affordable cost, that the industry of the horse-drawn carriage passed away. These two Lancet studies show that those who practise conventional tissue reconstruction and organ transplantation, and the health-care and commercial industries which support them, should finally be taking the quirky minnows of tissue engineering quite seriously. Disruptive innovation might be nigh. *Martin A Birchall, Alexander M Seifalian UCL Ear Institute, Royal National Throat Nose and Ear Hospital, London WC1X 8DA, UK (MAB); Nanotechnology and Regenerative Medicine, Division of Surgery and Interventional Science, University College London, Royal Free London NHS Foundation Trust Hospital, London, UK (AMS) [email protected] We declare that we have no competing interests. 1
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7 8 9
10 11 12
Raya-Rivera AM, Esquiliano D, Fierro-Pastran R, et al. Tissue-engineered autologous vaginal organs in patients: a pilot cohort study. Lancet 2014; published online April 11. http://dx.doi.org/10.1016/S01406736(14)60542-0. Fulco I, Miot S, Haug MD, et al. Engineered autologous cartilage tissue for nasal reconstruction after tumour resection: an observational first-inhuman trial. Lancet 2014; published online April 11. http://dx.doi. org/10.1016/S0140-6736(14)60544-4. Badylak SF, Taylor D, Uygun K. Whole-organ tissue engineering: decellularization and recellularization of three-dimensional matrix scaffolds. Annu Rev Biomed Eng 2011; 13: 27–53. Centanni JM, Straseski JA, Wicks A, et al. StrataGraft skin substitute is well-tolerated and is not acutely immunogenic in patients with traumatic wounds: results from a prospective, randomized, controlled dose escalation trial. Ann Surg 2011; 253: 672–83. Olausson M, Patil PB, Kuna VK, et al. Transplantation of an allogeneic vein bioengineered with autologous stem cells: a proof-of-concept study. Lancet 2012; 380: 230–37. Bhargava S, Patterson JM, Inman RD, MacNeil S, Chapple CR. Tissue-engineered buccal mucosa urethroplasty-clinical outcomes. Eur Urol 2008; 53: 1263–69. Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet 2006; 367: 1241–46. Delaere PR, Hermans R. Clinical transplantation of a tissue-engineered airway. Lancet 2009; 373: 717–18. Jabir S, Frew Q, El-Muttardi N, Dziewulski P. A systematic review of the applications of free tissue transfer in burns. Burns 2014; published online Feb 8. DOI:10.1016/j.burns.2014.01.008. Christensen CM, Bohmer R, Kenagy J. Will disruptive innovations cure health care? Harv Bus Rev 2000; 78: 102–12. Christensen CM. The innovator’s solution: creating and sustaining successful growth. Boston, MA: Harvard Business Press, 2003. de Mel A, Seifalian AM, Birchall MA. Orchestrating cell/material interactions for tissue engineering of surgical implants. Macromol Biosci 2012; 12: 1010–21.
www.thelancet.com Published online April 11, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60533-X
