Overview of the Development, Applications, and Future Perspectives

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Overview of the Development, Applications, and Future Perspectives of Decellularized Tissues and Organs Naoko Nakamura, Tsuyoshi Kimura, and Akio Kishida* Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062 Japan ABSTRACT: Decellularized tissues, in which the extracellular matrix is isolated, have broad applications as implantable biomaterials and/or biological scaffolds for tissue repair, and show good clinical performance. Decellularized tissue characteristics, such as their shape, structure, mechanical properties, and biological activity, are strongly affected by the decellularization protocol. The orthotopic implantation of decellularized tissues, a common procedure, typically induces cell infiltration and extracellular matrix (ECM) reconstruction resulting in tissues that resemble the source tissues. The ectopic implantation of decellularized tissues results in reconstruction that is either adapted to the implantation site or to the decellularized tissue source. In this review, the differences between methods are discussed. In addition, new methods aimed at extending the applications of decellularized tissues are discussed, particularly methods that confer novel functions to decellularized tissues, such as devices that link native tissues with artificial materials using decellularized tissue as an intermediate. KEYWORDS: decellularized tissue, decellularized organ, orthotopic, ectopic, complex, functionalization data.29 On the other hand, at 2014, this criticized researchers reported positive dates with 5-year follow-up results with showing CT scan images and histological and SEM images.30 At this stage, because there are no criteria for products of decellularized tissues and organs, it is difficult to judge what causes the negative results. The most important thing is to decide the criteria for products to ensure the clinical use of decellularized tissues and organs for long duration. In this paper, decellularization methods, orthotopic and ectopic in vivo performance, whole organ decellularization, and future applications of decellularized tissues are introduced.

1. INTRODUCTION Recent developments in decellularized tissue research have enabled their use in broad applications, e.g., as implantable biomaterials, tissue substitutes, and biological scaffolds for regenerative medicine. Decellularized tissues are prepared by removing cells from original tissues; they are used as-prepared or after they are processed into a sheet, thread, or powder. After decellularization, the shape, size, and complex structural properties of the tissue are maintained. The isolated extracellular matrix (ECM) can be used as a scaffold material consisting mainly of collagen. The ECM and its threedimensional (3D) structure are important for tissue regeneration. Decellularized tissues that maintain ECM components and structures may be ideal scaffolds for regeneration. In 1999, a clinical study of a decellularized porcine heart valve was initiated by CryoLife (Kennesaw, GA, USA), leading to the approval and commercialization of the first artificial heart valve in 2001. Since then, many decellularized tissue products have come to market,1−5 and those derived from allogeneic sources or xenogeneic sources, such as pigs, cows, and horses, are used in clinical applications (Table 1). Most of these products achieved success in clinical uses, and there are lots of reports for positive clinical data.6−30 However, there are also few reports for negative clinical data.8,28,29 For example, some researchers reported that it was not suitable to transplant the decellularized heart valve (e.g., SYNERGRAFT8 and Matrix P28) to children, showing the results of stenosis, rupture, immune rejection, or calcific deposits. At 2013, some of clinical uses for decellularized trachea are criticized with negative © XXXX American Chemical Society

2. DECELLULARIZATION METHODS Various decellularization methods have been developed. They are roughly classified into three groups as follows: chemical treatments (e.g., detergents, acids and bases, and alcohols), biological treatments (e.g., enzymes), and physical treatments (e.g., freezing and thawing, pressurization, and electroporation) (Figure 1). Cell removal is affected by various factors, such as the cell density, thickness, and lipid content of the original tissue. Therefore, it is important to determine which method or combination is most suitable for particular tissue types. The staining of tissue sections and DNA quantitation are usually Special Issue: Biomimetic Bioactive Biomaterials: The Next Generation of Implantable Devices Received: August 31, 2016 Accepted: November 17, 2016 Published: November 17, 2016 A

DOI: 10.1021/acsbiomaterials.6b00506 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

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ACS Biomaterials Science & Engineering Table 1. Summary of Commercially Available Decellularized Tissues products AlloDerm AlloMax AlloPatch HD ArthroFlex

company

SureDerm Fortiva

LifeCell Corp. Davol Inc. ConMed LifeNet Health Inc. Coloplast RTI Surgical Ethicon Mentor LifeCell Corp., KCI RTI Surgical LifeNet Health Inc. Biowel Sciences RTI Surgical

Medeor Matrix

DSM

Permacol Surgical Implant Strattice

Medtronic Inc.

XenMatrix

Davol Inc.

Collagen Repair Patch Meso BioMatrix

Zimmer Inc.

PriMatrix

TEI Biosciences, TEI Medical TEI Biosciences TEI Biosciences, Stryker Corp. Coloplast

Axis Cortiva FlexHD Structural FlexHD Pliable GraftJacket, GraftJacket Xpress Matrix HD Oracell

SurgiMend TissueMend Suspend

LifeCell Corp.

DSM

tissue source dermis dermis dermis dermis

soft tissue soft tissue tendon soft tissue

human human human human human

dermis dermis dermis dermis dermis

uterus soft tissue soft tissue breast soft tissue, chronic wound soft tissue dentistry

human dermis human dermis human dermis porcine dermis porcine dermis porcine dermis porcine dermis porcine dermis porcine dermis porcine mesothelium fetal bovine dermis bovine dermis bovine dermis human fascia lata

products

applications

human human human human

Acell Inc.

Oasis, Surgisis

Cook Biotech Inc. CorMatrix Cardiovascular Inc. IOP Inc.

CorMatrix ECM IOPatch CopiOs

soft tissue soft tissue soft tissue soft tissue soft tissue soft tissue soft tissue soft tissue soft tissue, tendon urethra

applications soft tissue

porcine SIS

pericardium, heart

human pericardium bovine pericardium bovine pericardium bovine pericardium

ophthalmology

bovine pericardium bovine pericardium human aorta human heart valve porcine heart valve porcine heart valve porcine heart valve Human bone/ cartilage

soft tissue

RTI Surgical

human bone

bone

RTI Surgical

human bone

bone

Tutopatch Veritas

Baxter

CryoPatch SG CryoValve SG

CryoLife Inc. CryoLife Inc.

Epic, SJM Biocor, Trifecta Freestyle, Hancock ll, Mosaic Matrix P plus N

St. Jude Medical Inc. Medtronic Inc.

Chondrofix Osteochondral Allograft AlloWedge, Biofoot, Elemax BioAdapt, map3

Zimmer Inc.

Perimount

tissue source porcine bladder porcine SIS

Zimmer Dental Inc. B. Braun Melsungen AG Edwards Lifesciences LLC RTI Surgical

Lyoplant

soft tissue soft tissue

company

MatriStem, Acell Vet

autotissue

soft tissue

dentistry dura mater valve replacement

soft tissue heart valve replacement valve replacement valve replacement valve replacement knee joint

Figure 1. Typical decellularization processes and their decellularization effectiveness and ECM damages.

used. SDS is a strong detergent that can remove nearly all tissue contents, except collagen. For minimal decellularization, a high hydrostatic pressure (HHP) method has been adopted. The HHP method is a unique physical method that can destroy cell membranes at over 2000 atm, microorganism membranes at over 6000 atm, and virus capsules at over 9000 atm. The porcine aortic intima-media was sectioned and decellularized using the two methods.31 Figure 2a shows differences in ECM structures using the two methods. The original lamellar elastin fibrils were crimped with small wavelike shapes. After decellularization, the HHP-treated samples were structurally similar to the untreated samples. However, the

performed to evaluate cell removal. Badylak et al. proposed quality standards for decellularization for clinical applications.3 They suggested a residual DNA length of less than 200 bp and DNA content of less than 50 ng/mg as standards.3 Although most studies of decellularized tissues have reported successful cell removal, the resulting ECM structures vary depending on precise methods. Comparisons of the structure, physical properties, and biological activity can clarify the differences among decellularized tissues. For these comparisons, it is useful to prepare two decellularized tissue types, one that is perfectly decellularized and another that is minimally decellularized. For perfect decellularization, SDS treatment is B


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Figure 2. Decellularized porcine aortic intima-media using HHP and SDS methods.31 (a) Histological characterization of the porcine aorta in the circumferential direction. Scale bars represent 50 μm. HHP: high hydrostatic pressurization; SDS: sodium dodecyl sulfate; HE: hematoxylin and eosin; EVG: Elastica-van Gieson. (b) Representative stress−strain curves of aortic intima-media in the longitudinal and circumferential directions. Reproduced with permission from ref 31. Copyright 2015 Oxford Journals.

Figure 3. Overview of tissue construction using decellularized tissues as a scaffold for orthotopic or ectopic implantation.

lamellar elastin fibrils of SDS-treated samples were straight and had large wave-like shapes. The interlamellar space of the SDStreated samples was enlarged, and the lamellar elastin fibrils at the intima surface appeared to be fragmented. Figure 2b summarizes the mechanical properties in the longitudinal and circumferential directions. HHP-treated samples retained the original mechanical properties, whereas SDS-treated samples were softer and weaker compared with the original samples. Based on these results, the decellularization method affected the ECM structure and, consequently, the mechanical properties. Similarly, relationships between tissue structure, protein permeability, and blood compatibility were examined.32 For this analysis, the decellularized porcine intima-media of the aorta

obtained by HHP and SDS methods were used, and the permeability of bovine serum albumin was measured. Permeability was higher for SDS-treated samples than original and HHP-treated samples. These results indicated that the decellularization methods affect protein permeability.7 A more detailed study was performed using various decellularization conditions. The porcine carotid artery was decellularized to prepare a small-diameter vascular graft with different HHP treatment conditions.33 After HHP treatment, the carotid artery was washed at two temperatures (37 and 4 °C). Based on a histological evaluation, the washing temperature clearly affected the collagen structure of the decellularized carotid artery. The amount of collagen decreased in the carotid artery decellularized by HHP and washed at 37 °C. However, C


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Figure 4. Decellularized tissuelike reconstruction by ectopic implantation.45 (A−D) X-ray micro CT images of decellularized cortical bone pairs at 1 and 2 weeks after ectopic implantation. White and black scale bars: 1 mm. (E) H&E staining of the gap between decellularized cortical bone pairs at 2 weeks after implantation. Small window (upper right) shows the expanded view. Reproduced with permission from ref 45. Copyright 2013 Japanese Society for Medical and Biological Engineering.

uterine tissues39 have been reconstructed using decellularized tissues. The preparation of decellularized corneas can be viewed as a typical example of decellularized tissue development for orthotopic use.40−42 The cornea is one of the most difficult tissues to decellularize without structural deformation. If the structure is destroyed, transparency will be lost. Accordingly, the use of detergents leads to translucence or dissolved corneal matrices. However, decellularized corneas have been obtained by HHP treatment. HHP-treated corneas maintain the ECM structure and mechanical properties of the original corneas. To evaluate performance, the decellularized cornea was implanted into rabbit cornea pockets and deep anterior lamellar keratoplasty was performed. Although the decellularized cornea was slightly translucent immediately after decellularization, the transparency was recovered over time after implantation. Based on fluorescein staining, re-epithelialization proceeded gradually, and was complete at 6 months after implantation. A histological evaluation showed that there was no neovascularization, downgrowth, or immune rejection. Corneal epithelial-like cells covered the decellularized cornea, and the infiltration of keratocytes to the decellularized cornea was observed. In this case, the decellularized tissue was an effective scaffold for the reconstruction of the original tissue when it was implanted at the orthotopic site. 3.2. Ectopic Performance. In clinical settings, decellularized tissues are often used at sites that differ from the decellularized tissue source; this is referred to as ectopic implantation. The dermis is one of the most common tissue sources for decellularized tissue products. These decellularized tissues are used not only as dermal alternatives, but also for many soft tissue prostheses and substitutes, including in hernia repairs,12−14 breast reconstruction postmastectomy,15−17 periodontal tissue reconstruction,18−21 and rotator cuff tendon repair.22−27,43 Although the 3-D ECM structures of the dermis are different from those of the breast, gingiva, and tendon, each of these tissues can be reconstructed using the decellularized dermis. The tendon, for example, requires sufficient strength to connect bone and muscle, and the dermis does not have this function. However, many researchers have reconstructed the tendon using decellularized dermis, with sufficient function.22,24−26 To function effectively as a tendon, the decellularized dermis has to be reconstructed as a tendon-like tissue. This means that the cells around the implantation site regenerated the 3-D ECM structure of tendon tissues using the decellularized dermis as a scaffold. The use of the decellularized dermis in this case suggests that the 3D ECM structures of

the quantity and structure of collagen were preserved in the carotid artery washed at 4 °C after HHP treatment. In rat carotid artery syngeneic transplantation, HHP/37 °C decellularized carotid arteries occluded after 2 weeks, but HHP/4 °C decellularized arteries did not. These results indicate that structural alterations of decellularized tissues affect in vivo performance. Typically, a goal of decellularization is to maintain the ECM structure as much as possible. However, it is difficult to avoid ECM damage. There are no criteria that how much ECM volume should be maintained. For comparing the ECM damages, researchers have to prepare decellularized tissues using several decellularization methods by themselves. Most reports showed only one decellularization method, with not comparing ECM damages. Despite extensive damage that results, detergent-based methods are widely used, because detergent-based method is simple and dose not need specific facilities. By another perspective, there is no evidence to show that whole original ECM is necessary for reconstruction of all kind of tissues and organs. Before starting to prepare the decellularized tissues and organs, researchers need to consider what kind of decellularization method is suitable for their objective. It is necessary to choose appropriate decellularization methods considering the application and properties of the decellularized tissues.

3. ORTHOTOPIC AND ECTOPIC IN VIVO PERFORMANCE OF DECELLULARIZED TISSUE Decellularized tissues are used in many clinical applications, both orthotopically and ectopically (Figure 3). Briefly, decellularized tissues are implanted to a site lacking the tissue, and the reconstructed tissue exhibits similar properties to those of the source (orthotopic reconstruction). Alternatively, the decellularized tissues can be implanted ectopically. In this case, the decellularized tissues are derived from an entirely different site than the implantation site, e.g., dermal tissues are implanted in tendons. Two responses are observed: the construction of tissue is adapted to the implantation site or the reconstruction of decellularized tissues resembles the decellularized tissue source. There were no reports for the relationship of decellularized tissues and implantation site. These perspectives will provide researchers good opportunities to consider how ECM works in the body. 3.1. Orthotopic Performance. The simplest utilization of decellularized tissue is in orthotopic reconstruction. For example, heart valves,7−10,34 vessels,11,33,35−37 bone,38 and D


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and the recellularized hearts exhibited spontaneous contractions, generated mechanical force, and were responsive to drugs, although they were not sufficient for normal heart functions.47 In addition, the usage of cells derived from iPSCs, which can differentiate into appropriate cells as necessary, would address the problem of cell source because it eliminates the need to harvest specific cells from patients.

decellularized tissues are not closely dependent on their original functions; ectopic tissue construction is adapted to the implantation site. 3.3. Ectopic Tissue Reconstruction. Many research and clinical studies have reported that when decellularized tissues are implanted to orthotopic or ectopic sites, appropriate tissues for the implantation site are constructed, irrespective of the decellularized tissue source. It is thought that the cells that exist around the implantation site are induced and play an important role in tissue constructions. Some studies have revealed that ectopic remodeling is accomplished when decellularized tissues maintain the ECM structure of the original tissue.44,45 For example, decellularized cortical bone induces osteogenesis ectopically (Figure 4).45 In this example, fragments of HHP-decellularized femur cortical bone were assembled into pairs and fastened together using suture thread. They were implanted in rats subcutaneously to investigate the ectopic response. After implantation, few immune reactions were observed, but the bone fragments were not absorbed. At 2 and 4 weeks after implantation, a gap between the two fragments was observed. The gap was not discernible in X-ray micro CT images, and a bonelike collagen matrix was observed in the gap based on histological analyses. These observations suggested that the assembled HHPdecellularized bone fragments induce the formation of bone matrix to fill the gap, even if they are located in an ectopic environment. Bone matrix formation normally occurs via osteoblasts, which exist on the bone surface, not in subcutaneous regions. Therefore, it is possible that mesenchymal stem cells migrate to the preserved microenvironment of the decellularized matrix. Accordingly, decellularized tissues could control cells to ensure ectopic localization and differentiation to functional cells in order to reconstruct bone. To achieve the ectopic reconstruction of tissues that are similar to the decellularized tissue source, various conditions are important, such as the combination of decellularized tissue type and the tissue type at the implantation site as well as the maintenance of ECM components and structures after decellularization. Future analyses of this model are needed to clarify the concept of tissue engineering in which implanted materials can control cell functions.

5. FUNCTIONALIZATION OF DECELLULARIZED TISSUES USING ARTIFICIAL MATERIALS FOR WIDE APPLICATIONS Some groups have started to functionalize decellularized tissues by combining them with artificial materials to promote functions that were compromised by the decellularization process (Figure 5). For example, it is well-known that

Figure 5. Overview of additional processing methods, such as in vitro recellularization and functionalization, before decellularized tissue and organ use in vivo.

endothelium of blood vessel is important for prevention of blood coagulation. However, decellularization process sometimes removes endothelial blood cells and sometimes damages the basement membrane of endothelium, although the degree of damages is of course depends on decellularization method. They would need to treatment in order to cover the endothelium surface by the endothelial blood cells as soon as transplantation. To prevent blood coagulation inside decellularized blood vessels or capillary vessels in decellularized organs, some researchers have used the immobilization of anticoagulants, such as heparin62−64 or peptides,65 to the endothelium of the decellularized vessel. To make decellularized tissues work the same as native tissue, these functionalizations might be needed. Other researchers have attempted to develop novel devices for decellularized tissue using artificial materials.66−68 The development of a device that links native tissues and artificial materials with decellularized tissues, without compatibility issues, is potentially useful. Artificial materials have different mechanical properties from those of native tissues. Polymer materials, e.g., silicone or polyethylene terephthalate, are used in clinical applications as transdermal devices (for example, to connect catheters). These materials have low compatibility with native tissues. This occasionally induces epidermal downgrowth. To resolve these problems, hydroxyapatite and titanium mesh coatings have been applied to transdermal

4. DECELLULARIZED WHOLE ORGANS Most studies of decellularization focus on tissues, with the objective of developing replacement materials for particular tissues or to compensate for the loss of tissues and/or organs. Some researchers have recently reported the successful decellularization of whole organs, such as the heart,46−49 liver,50−54 lung,55−59 and kidney,60,61 for whole organ replacement. To prepare decellularized whole organs, vascular networks from large-diameter vessels to capillary vessels were used. Detergents were perfused using these vascular networks for decellularization, and these vascular networks were then used to supply nutrition to whole organs. In the case of in vitro recellularization, these vascular networks have often been used for cell injections and culturing to promote cellular distribution throughout decellularized organs. The first reconstruction of a decellularized organ was reported by Ott et al.46 They prepared decellularized rat hearts, seeded myocardial cells, and succeeded in partially reproducing heart function, including electrophysiological properties. In 2013, Ying et al. seeded multipotent cardiovascular progenitor cells derived from human induced pluripotent stem cells (iPSCs) into decellularized mouse hearts, E


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Figure 6. Functionalization of decellularized tissues.66 (a) Complex with the decellularized dermis and PMMA polymer. SEM images show cross sections of samples. (b) Stress−strain curves of the native dermis, decellularized dermis, decellularized dermis/PMMA complex, and bulk PMMA. (c) Gradient complex with the decellularized dermis and PMMA. (B-D) X-ray micro CT and 3-D-reconstructed images of the gradient complex. White parts show the PMMA immersion area. (E) H&E staining of the gradient complex after subcutaneous implantation. Reproduced with permission from ref 66. Copyright 2014 Elsevier.

These results suggested that the decellularized dermis and PMMA gradient complex could prevent epidermal downgrowth. Therefore, this complex model is expected to extend the applications of decellularized tissue. Furthermore, to realize the ideal complex and to apply them for the several applications, researchers should investigate in detail the interface between ECM and artificial materials inside the decellularized tissue. Decellularized tissues consist of several complicated and ununiformed ECMs, including those of hydrophilic and hydrophobic nature. It is difficult to select what kind of artificial materials should be used and to control the composition of the artificial materials and decellularized tissue. There are two approaches to solve these issues. One is that the artificial material, which is compatible with ECM, is selected to be suitable for ECM characteristics. The second approach is that ECM is modified to be suitable for artificial material. For example, as describe above, the decellularization methods have differences in removing and remaining the ECM. By focusing on these differences, it would be able to control the removing and remaining of selective ECM to be suitable for artificial materials. Either way, because there is not enough knowledge for functionalization of decellularized tissue and organs, it should reveal the interaction between ECM and artificial materials.

devises. Although these substances improve the adhesion of native tissues and artificial materials, they cannot resolve the differences in mechanical properties. These differences result in a concentration of stress at the interface of native and artificial tissues, and eventually result in dermal damage. A linking device for native tissues and artificial materials that uses decellularized tissue as an intermediate material, and ensures compatibility between native tissue and artificial materials at the molecular level has been reported. In the study, as an artificial material, poly(methyl methacrylate) (PMMA) was used. The decellularized dermis was immersed in MMA monomers, and the decellularized dermis and PMMA complex was prepared by polymerization (Figure 6). A compression test showed that the composite had an intermediate value between those of the dermis and PMMA, and the elasticity of the complex was similar to that of the dermis. These results indicate that mechanical properties of the dermis were maintained after combining with PMMA. It was inferred that the PMMA composition varied in the complex with the decellularized dermis. To prepare a gradient complex with the decellularized dermis and PMMA, MMA was injected into the center of decellularized dermis, which was cylindrical with a hole at the center. MMA expanded from the center to the outside at a gradient, and a complex exhibiting a gradient was prepared. When the whole complex, and not the gradient complex, was implanted subcutaneously into rats, epidermal down-growth was observed. In the case of the gradient complex, integration with surrounding tissues by infiltration of the host cells to the decellularized dermis was observed.

6. SUMMARY Decellularized tissues and organs have been studied extensively and are already used in clinical applications. Studies of decellularized tissues and organs are advancing in scope. As F


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(12) Kolker, A. R.; Brown, D. J.; Redstone, J. S.; Scarpinato, V. M.; Wallack, M. K. Multilayer reconstruction of abdominal wall defects with acellular dermal allograft (AlloDerm) and component separation. Ann. Plast. Surg. 2005, 55 (1), 36−42. (13) Blatnik, J.; Jin, J.; Rosen, M. Abdominal hernia repair with bridging acellular dermal matrix–an expensive hernia sac. Am. J. Surg. 2008, 196 (1), 47−50. (14) Misra, S.; Raj, P. K.; Tarr, S. M.; Treat, R. C. Results of AlloDerm use in abdominal hernia repair. Hernia 2008, 12 (3), 247− 250. (15) Gamboa-Bobadilla, G. M. Implant breast reconstruction using acellular dermal matrix. Ann. Plast. Surg. 2006, 56 (1), 22−25. (16) Rawlani, V.; Buck, D. W., 2nd.; Johnson, S. A.; Heyer, K. S.; Kim, J. Y. Tissue expander breast reconstruction using prehydrated human acellular dermis. Ann. Plast. Surg. 2011, 66 (6), 593−597. (17) Brooke, S.; Mesa, J.; Uluer, M.; Michelotti, B.; Moyer, K.; Neves, R.; Mackay, D.; Potochny, J. Complications in tissue expander breast reconstruction: a comparison of AlloDerm, DermaMatrix, and FlexHD acellular inferior pole dermal slings. Ann. Plast. Surg. 2012, 69 (4), 347−349. (18) Wei, P. C.; Laurell, L.; Geivelis, M.; Lingen, M. W.; Maddalozzo, D. Acellular dermal matrix allografts to achieve increased attached gingiva. Part 1. A clinical study. J. Periodontol. 2000, 71 (8), 1297− 1305. (19) Aichelmann-Reidy, M. E.; Yukna, R. A.; Evans, G. H.; Nasr, H. F.; Mayer, E. T. Clinical evaluation of acellular allograft dermis for the treatment of human gingival recession. J. Periodontol. 2001, 72 (8), 998−1005. (20) Tal, H.; Moses, O.; Zohar, R.; Meir, H.; Nemcovsky, C. Root coverage of advanced gingival recession: a comparative study between acellular dermal matrix allograft and subepithelial connective tissue grafts. J. Periodontol. 2002, 73 (12), 1405−1411. (21) Cole, P.; Horn, T. W.; Thaller, S. The use of decellularized dermal grafting (AlloDerm) in persistent oro-nasal fistulas after tertiary cleft palate repair. J. Craniofac. Surg. 2006, 17 (4), 636−641. (22) DiDomenico, L. A.; Williams, K.; Petrolla, A. F. Spontaneous rupture of the anterior tibial tendon in a diabetic patient: results of operative treatment. J. Foot Ankle Surg. 2008, 47 (5), 463−467. (23) Snyder, S. J.; Arnoczky, S. P.; Bond, J. L.; Dopirak, R. Histologic evaluation of a biopsy specimen obtained 3 months after rotator cuff augmentation with GraftJacket Matrix. Arthroscopy 2009, 25 (3), 329− 333. (24) Longo, U. G.; Lamberti, A.; Maffulli, N.; Denaro, V. Tendon augmentation grafts: a systematic review. Br. Med. Bull. 2010, 94, 165− 188. (25) Barber, F. A.; Burns, J. P.; Deutsch, A.; Labbé, M. R.; Litchfield, R. B. A prospective, randomized evaluation of acellular human dermal matrix augmentation for arthroscopic rotator cuff repair. Arthroscopy 2012, 28 (1), 8−15. (26) Agrawal, V. Healing rates for challenging rotator cuff tears utilizing an acellular human dermal reinforcement graft. Int. J. Shoulder Surg. 2012, 6 (2), 36−44. (27) Protzman, N. M.; Stopyra, G. A.; Hoffman, J. K. Biologically enhanced healing of the human rotator cuff: 8-month postoperative histological evaluation. Orthopedics 2013, 36 (1), 38−41. (28) Voges, I.; Bräsen, J. H.; Entenmann, A.; Scheid, M.; Scheewe, J.; Fischer, G.; Hart, C.; Andrade, A.; Pham, H. M.; Kramer, H. H.; Rickers, C. Adverse results of a decellularized tissue-engineered pulmonary valve in humans assessed with magnetic resonance imaging. Eur. J. Cardiothorac Surg. 2013, 44 (4), 272−279. (29) Vogel, G. Trachea transplants test the limits. Science 2013, 340 (6130), 266−268. (30) Gonfiotti, A.; Jaus, M. O.; Barale, D.; Baiguera, S.; Comin, C.; Lavorini, F.; Fontana, G.; Sibila, O.; Rombolà, G.; Jungebluth, P.; Macchiarini, P. The first tissue-engineered airway transplantation: 5year follow-up results. Lancet 2014, 383 (9913), 238−244. (31) Wu, P.; Nakamura, N.; Kimura, T.; Nam, K.; Fujisato, T.; Funamoto, S.; Higami, T.; Kishida, A. Decellularized porcine aortic

ectopic tissue reconstruction depends on decellularized tissues, the ECM derived from decellularized tissues controls host cells and accordingly is a primary determinant of reconstruction success. In this model, the ECM is not just a scaffold for cells, but the control center of cell functions or a niche for more complex biological functions. It is necessary to determine the properties of decellularized tissues that are associated with reconstruction outcomes. The development of decellularized tissues and organs with added benefits, such as functionalization via artificial materials, is an important goal of future research.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported in part by JSPS KAKENHI Grant JP16K21015. We thank Editage (www.editage.jp) for English language editing.

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REFERENCES

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