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Fibrin glue as the cell-delivery vehicle for mesenchymal stromal cells in regenerative medicine
Cytotherapy, 2012; 14: 555–562
Fibrin glue as the cell-delivery vehicle for mesenchymal stromal cells in regenerative medicine
XIUWEN WU, JIANAN REN & JIESHOU LI
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Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China Abstract The use of tissue-engineering techniques such as stem-cell therapy to renew injured tissues is a promising strategy in regenerative medicine. As a cell-delivery vehicle, fibrin glues (FG) facilitate cell attachment, growth and differentiation and, ultimately, tissue formation and organization by its three-dimensional structure. Numerous studies have provided evidence that stromal cells derived from bone marrow (bone marrow stromal cells; BMSC) and adipose tissue (adiposederived stromal cells; ADSC) contain a population of adult multipotent mesenchymal stromal cells (MSC) and endothelial progenitor cells that can differentiate into several lineages. By combining MSC with FG, the implantation could take advantage of the mutual benefits. Researchers and physicians have pinned their hopes on stem cells for developing novel approaches in regenerative medicine. This review focuses on the therapeutic potential of MSC with FG in bone defect reconstruction, cartilage and tendon injury repair, ligament, heart and nerve regeneration, and, furthermore, wound healing. Key Words: adipose-derived stromal cells, bone-marrow derived stromal cells, fibrin glues, mesenchymal stromal cells, regenerative medicine
Introduction Regenerative medicine is an alternative approach for replacing or regenerating tissue damage and organ loss. The strategies that promote tissue regeneration, instead of damaged tissue substitution, are usually based on the use of tissue-engineering techniques. The tissue-engineering approach in this review, which combines stem cells and fibrin glue (FG), provides a biocompatible scaffold material for the renewing cell sources. Stem cells are characterized by the ability to differentiate into many lineage-specific cell types. With the development of two of the technologies that allow the isolation of stem cells, monoclonal antibodies and high-speed sorting of cells, stem cells are currently major cell sources in tissue engineering (1). Despite the pluripotency of embryonic fetal stem cells, research has been driven toward adult stem cells for use in tissue repair and regeneration, because of ethical, regulatory and availability concerns (2).
Several organs and tissues, such as skin (3), blood vessels (4), brain (5), skeletal muscle (6), liver (5), testis (7) and pancreas (5), have shown the existence of adult stem cells. Among the many available sources, mesenchymal stromal cells (MSC) derived from bone marrow or adipose tissue are commonly used as multipotent autologous cell sources and can be collected through relatively non-invasive methods (5). Among MSC, bone marrow stromal cells (BMSC) have been considered the major source for many years in the field of tissue engineering (2). However, because of the ease of harvest and abundance, adipose-derived stromal cells (ADSC) are also regarded as attractive, readily available adult stem cells, and have become increasingly popular for use in many applications (2).
Characterization of MSC MSC are identified through a combination of physical, phenotypic and functional properties (8):
Correspondence: Jianan Ren, Department of Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, PR China. E-mail: [email protected] (Received 1 September 2011; accepted 3 November 2011) ISSN 1465-3249 print/ISSN 1477-2566 online © 2012 Informa Healthcare DOI: 10.3109/14653249.2011.638914
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(a) adherence to plastic; (b) specific surface antigen expression; (c) multipotent differentiation potential to diverse lineages such as osteoblasts, adipocytes, chondroblasts, cartilage, muscle and neuronal-like cells. Surface antigen expression has been used extensively in immunology. Typical categories of surface marker proteins expressed in MSC include: adhesion molecules such as integrins (CD29, CD49e), receptor molecules such as hyaluronate (CD44), cadherins (CD144), surface enzymes (CD73), extracellular matrix proteins (CD90, CD105), intercellular adhesion molecules (CD54), vascular adhesion molecules (CD106), complement regulatory proteins, and histocompatibility antigens (9). MSC may be typically negative for CD45, CD34, CD31 and CD14, and positive for CD13, CD29, CD44, CD49e, CD54, CD55, CD63, CD73, CD90, CD105, CD106, CD144, CD146, CD166 and human leukocyte antigen (HLA). This phenotype is valid for both human and murine cells, with the exception of CD34, which may be positive in some murine MSC samples and may be positive very early in human cultures but very rapidly lost (10). The cluster of differentiation
(CD) marker list of ADSC and BMSC is shown in Table I. FG as the cell-delivery vehicle Adult stem cells require an appropriate scaffold to facilitate cell attachment, growth and differentiation, and, ultimately, tissue formation and organization. The presence and properties of these scaffolds, which are primarily hydrogels such as FG (11–13) and platelet-rich gels (14), can greatly influence cell survival and differentiation. Stacey et al. (15) observed a markedly decreased differentiation in two-dimensional (2-D) cultures compared with three-dimensional (3-D) scaffolds. Among 3-D scaffolds, including platelet-poor plasma, alginate, fibrin gel and collagen sponge, fibrin gel showed an optimal combination of mechanical characteristics and support of MSC differentiation and angiogenic factor secretion (16). The use of FG was advocated in tissue engineering for its 3-D characteristics, providing appropriate cells with contact with the culture environment through their surfaces.
Table I. Cell marker list of ADSC, BMSC and mouse ADSC or BMSC.
Positive markers
Negative markers
Surface marker
ADSC (9,100–104) Human
BMSC (82,101,103,104) Human
ADSC or BMSC (82) Mouse
CD13 CD29 CD44 CD49e CD54 CD55 CD63 CD73 CD90 CD105 CD106 CD144 CD146 CD166 HLA-ABC CD11b CD14 CD19 CD31 CD34 CD45 Stro-1 CD3 CD117 CD62L CD95L
⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ − ⫹ ⫹ ⫹ ⫹ − − − ⫹ /− ⫹/− − ⫹/− − − − −
⫹ ⫹ ⫹/− ⫹ ⫹ ⫹ ⫹ ⫹ ⫹/− ⫹ ⫹/− ⫹ ⫹ ⫹ ⫹
⫹/− ⫹ ⫹/−
–
⫹/−
− ⫹/− − ⫹/− − − − −
− ⫹/− −
⫹/− ⫹ ⫹
−
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Implantation of MSC with fibrin glue carriers In addition to the 3-D structures, FG combine some important advantages such as high seeding efficiency, uniform cell distribution (17) and adhesion capabilities (18). FG is non-cytotoxic, and is a naturally porous physiologic scaffold that can stimulate cell adhesion and growth (19,20). Furthermore, when produced from the patient’s own blood, it could be used as an autologous scaffold without the potential risk of foreign body reaction or infection (21). Consisting of component I (fibrinogen and factor XIII) and component II (thrombin and calcium chloride), FG mimics the final stages of blood coagulation. Currently commercial allogeneic fibrin sealants are in clinical use, particularly for those patients whose clinical condition contraindicates an autologous procedure. Because of continued concerns over the cost and safety of commercial preparations, home-made FG are still attractive in spite of their low concentrations of fibrinogen. Concentrated fibrinogen could be obtained from a single unit of plasma by several methods, including cryoprecipitation, ammonium sulfate solution, ethanol precipitation and ethylene glycol precipitation (22). Cryoprecipitation can be performed with different freeze–thaw cycles; it is time-consuming but does not require the addition of exogenous chemicals. Although chemical precipitations result in a rapid procedure and high bond strength (23), the purity of the final product is a concern (24). Entirely autologous FG usually use thrombin produced from human plasma, rather than bovine origin, in order to avoid the possible formation of antibodies, which cross-react with the patient’s coagulation factor (25). Clinical applications A number of studies have demonstrated the advantages of using MSC for the repair and regeneration of multiple tissue types (26–33). FG in combination with an appropriate MSC source has been used in a variety of tissue-engineering applications, including bone defect reconstruction, cartilage and tendon injury repair, and ligament, heart and nerve regeneration. In addition, FG has been used to promote the healing of severe burns and chronic wounds. Furthermore, FG combined with ADSC is under clinical trials for chronic intestinal fistulae, including Crohn’s disease-related fistulae. Orthopedics Bone substitutes Fibrin sealants have provided the angiogenic basis of a composite graft to bone tissue and initial differentiation site for undifferentiated cells (34,35). Several authors have demonstrated that a fibrin matrix is
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an optimal support for transplanted MSC to obtain osseous defect regeneration. The ideal bone substitute should be biocompatible, biodegradable at the expense of bone growth, and moldable, with sufficient mechanical properties to fill and restore bone defects (36). As a biologic scaffold, however, FG has two major disadvantages: rapid degradation and low mechanical strength. To solve the first problem fibrinolytic inhibitor can be added, preventing the lysis of clots. One way to deal with the second problem is to elevate the concentration of fibrinogen, which is decided by the concentration of fibrinogen in the blood. Another way is to combine bioceramics with fibrin sealant, resulting in accumulated properties. The physical, chemical and biologic properties of both bioceramics and FG may be combined for preparing advanced bone substitutes (19). The association of bioceramics, fibrin sealants and stem cells may develop the clinical applications of bone substitutes. An in vitro study from Leong et al. (37) substantiated the potential of ADSC as a source of osteogenically capable progenitor cells in a 3-D fibrin/collagen matrix. Cui et al. (38) found that the calcium phosphate cement–FG composite supported BMSC attachment and proliferation. Several studies with experimental animals have demonstrated that fibrin sealants can provide a good scaffold containing numerous growth factors for proliferation of osteoinduced BMSC (39,40). Ito et al. (39) showed an increase in bone regeneration in a canine mandibular defect using MSC–platelet-rich plasma (PRP)–FG hybrid constructs, compared with MSC–FG constructs alone after 4 and 8 weeks. A combination of autologous platelet-rich FG (PRFG) with BMSC and MEDPOR (Porex Medical, Fairburn, GA, USA) as guided tissue regeneration could act as an osteogenic substitute (40). Tendon and ligament repair As well as bone substitutes, the use of autologous BMSC to repair experimental injuries of tendons and ligaments has been described amply in experimental animals (41,42). In 2003, Smith et al. (43) suggested for the first time the use of autologous mesenchymal cells obtained from bone marrow in spontaneous tendon lesions in horses. It was postulated that the biomechanical properties and histologic appearances of injured tissues were improved because of MSCmediated repair (41,44,45). A preliminary study from Lacitignola et al. (46) demonstrated that BMSC implantation combined with FG results in an effective clinical and ultrasound healing for tendon injury. Crovace et al. (47) described for the first time the efficacy of bone
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marrow-derived mononuclear cell (BMMNC) suspended in FG in an equine model of experimental tendinitis. The use of BMMNC is a simpler and more cost-e ective method than the use of cultured BMSC, thus resulting in its significant role in the future of tendon injury treatment.
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Cartilage reconstruction Human articular cartilage has limited repair potential (48). With the application of tissue-engineered cartilage, numerous pre-clinical studies have reported the development of hyaline-like tissue from autologous culture-expanded BMSC (49,50), and some have shown superior functionality of BMSC over chondrocytes (51,52). All these results have pushed MSC-based cartilage repair into clinical trials. Several clinical trials have reported the use of BMSC in articular cartilage defects (53–56). Haleem et al. (57) demonstrated that patients with osteochondral defects that were reconstructed with BMSC with a PRFG carrier experienced significant improvement in their functional knee scores and magnetic resonance imaging (MRI) findings as early as 6 months and maintained over 12 months post-operatively. Dragoo et al. (58) found that implanted ADSC developed the early functional characteristics of native hyaline cartilage in animal models, demonstrating themselves as promising cells for autologous cartilage regeneration. Cardiac functions Cardiac tissue engineering may provide an alternative treatment rather than replacing the damaged tissue. FG has several advantages as a cell scaffold for cardiovascular tissue engineering, such as a high seeding efficiency and uniform cell distribution (59). Furthermore, FG can be modified to facilitate its functionality in the myocardium (60–62). Christman et al. (63) stated that injection of FG alone could preserve infarct wall thickness and cardiac function. Angiogenesis is thought to salvage at-risk cardiomyocytes and enhance the survival of donor stem cells by improving the blood circulation in the infarction regions. Providing a suitable matrix environment for endothelial cell migration and branching morphogenesis (64), fibrin improves the microenvironment by inducing angiogenesis. In recent research by Guo et al. (59), heart function was significantly improved in rats receiving BMSC with FG, compared with BMSC transplantation alone and FG transplantation alone. Besides the enhancement of angiogenesis, FG gave the cells a temporary semirigid scaffold after transplantation, protecting BMSC resistance to hypoxia. All these cytoprotective effects
of FG are beneficial for the survival and differentiation of BMSC. Zhang et al. (65) transplanted ADSC combined with FG in rat infraction models and reported that the heart function improved significantly in the fibrin ⫹ ADSC group. This is the first study that has been devoted to demonstrating the therapeutic potential of ADSC and FG in the management of myocardial infarction. Nerve regeneration FG seeded with regenerative cells could be constructed as a bioresorbable nerve, which could guide regenerating axons without inhibiting the process of growth and maturation (66). With good tissue acceptance and a porous structure, the fibrin conduit allows neurotrophic growth factors to penetrate into the lumen. The degradation of the fibrin within 4 weeks also avoids compression syndromes and enhances biocompatibility (13). Recently, it has been shown that autologous FG is beneficial for peripheral nerve regeneration in an experimental rabbit model (67). Kalbermatten et al. (68) also used fibrin as a new nerve guide and bridged nerve defects. All these studies suggest a clinically interesting role for the new fibrin conduit during the initial phase of peripheral nerve regeneration. This application of ADSC and BMSC in promoting peripheral nerve regeneration is promising. In vivo research has demonstrated that MSC can be differentiated into cells that are Schwann cell-like, and can physically engraft and myelineate regenerating axons, thus enhancing nerve regeneration (69–71). Stem cells could also improve regeneration with the release of soluble nerve growth factors such as brain-derived neurotrophic factor (72) and angiogenic molecules, including vascular endothelial growth factor (VEGF) (73). Promising results have been achieved with the combination of regenerative cells and fibrin conduit, which are hopeful steps toward future clinical applications in the case of peripheral nerve injury. di Summa et al. (74) found that fibrin seeded with Schwann cells differentiated from ADSC-enhanced axonal regeneration. Wound repair Angiogenesis, immunity and epithelial cover are the three keys to healing and soft tissue maturation (75). It has been demonstrated clearly that fibrin matrix leads directly to angiogenesis (76), constitutes a natural support to immunity, and guides the coverage of injured tissues (75), featuring all the necessary parameters permitting optimal healing.
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Implantation of MSC with fibrin glue carriers The ability of stem cells to promote angiogenesis, secrete growth factors and differentiate into multiple cell types, may provide their role in promoting wound repair when combined with fibrin matrix (77). It has been demonstrated that BMSC are progenitors of wound-healing cells, such as fibroblasts (78), keratinocytes (79) and fibrocytes (80), which produce cytokines and orchestrate a cascade of events (81– 83). In addition, BMSC influences the structure of scar tissue for its secretion of collagen type III. Collagen type III may be secreted by BMSC (84), which is elevated to a ratio of 1:2 to collagen type I during the wound-healing process. Both ADSC and BMSC can accelerate the reepithelization of cutaneous wounds (12,85,86). Direct cell-to-cell contact and secretory-induced paracrine activation may be the two ways that ADSC promotes human dermal fibroblast proliferation (85,86). As a critical regulator of angiogenesis in wound healing (87,88), VEGF has a positive effect on wound repair. Ebrahimian et al. (89) also stated that ADSC has the potential to differentiate into keratinocytes, and to produce keratinocyte growth factor (KGF) as well as VEGF. Chronic wounds Chronic wounds include venous ulcers, pressure ulcers and diabetic ulcers (90), which present a major challenge in modern medicine. An innovative approach that delivers growth factors, such as plateletderived growth factor (91), insulin like growth factor-I (92) and fibroblasts (93), has been developed in the last few years. However, only limited success has been demonstrated in studies using these growth factors (94). On the other hand, several studies have evaluated the potential therapeutic effects of MSC on wound healing. The fibrin matrix, which provides a scaffold for the ADSC, permits improvement in the timing of chronic wound healing (95). Full-thickness skin defect wounds of pigs were achieved by local implantation of ADSC. Falanga et al. (12) showed complete closure of human chronic wounds after 7 weeks with a fibrin spray delivery of BMSC. In recent years, the combination of BMSC and PRFG has been demonstrated to synergize chronic wound healing in patients with diabetic wounds, taking advantage of the mutual benefits (96). An increase in tissue vascularization was reported in each of these cases and was thought to be an important component of the activity. Intestinal fistulae The application of ADSC along with FG in the healing of chronic fistulae from Crohn’s disease was
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the first phase I clinical trial of ADSC therapy (97). Cultured for between 6 and 31 days, ADSC was inoculated in four patients with nine fistulae. Seventyfive per cent of the fistulae (6/8) showed complete healing within 8 weeks of follow-up. After promising results with a phase I trial of treatment of perianal complex fistulae with ADSC, a phase II clinical trial evaluated the safety and efficacy of this novel therapy. The proportion of patients with fistulae healing was significantly higher for ADSC (71%), recurrences in the first year were rare and no treatment-associated adverse effects were reported (98). Subsequent histologic and electron microscopic results showed fistulae healing at the implanted areas; what was more, there were no signs of rejection or presence of tumor cells or neoplastic processes, regarding the safety of this innovative therapy (99). Conclusions In conclusion, it is likely that BMSC and ADSC with fibrin scaffolds will have extensive applications in the future. However, a number of challenges still remain before the therapy can be used in everyday clinical practice. A greater understanding of the mechanisms of interaction among MSC, growth factors and fibrin matrix regarding tissue regeneration is needed to advance the clinical utility of this therapy. Given that the potential risks of applying stem cells, additional studies are required on the safety of clinical tissue regeneration. Acknowledgments This work was supported by a grant from Climb Program in Natural Science Foundation for Distinguished Scholars, Jiangsu, China (BK2010017). Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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73. Rehman J, Traktuev D, Li J, Merfeld-Clauss S, TemmGrove CJ, Bovenkerk JE, et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation. 2004;109:1292–8. 74. di Summa PG, Kingham PJ, Raffoul W, Wiberg M, Terenghi G, Kalbermatten DF. Adipose-derived stem cells enhance peripheral nerve regeneration. J Plast Reconstr Aesthet Surg. 2010;63:1544–52. 75. Choukroun J, Diss A, Simonpieri A, Girard MO, Schoeffler C, Dohan SL, et al. Platelet-rich fibrin (PRF): a second-generation platelet concentrate. IV. Clinical effects on tissue healing. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;101:e56–60. 76. Dvorak HF, Harvey VS, Estrella P, Brown LF, McDonagh J, Dvorak AM. Fibrin containing gels induce angiogenesis. Implications for tumor stroma generation and wound healing. Lab Invest. 1987;57:673–86. 77. Cherubino M, Rubin JP, Miljkovic N, Kelmendi-Doko A, Marra KG. Adipose-derived stem cells for wound healing applications. Ann Plast Surg. 2011;66:210–5. 78. Ishii G, Sangai T, Sugiyama K, Ito T, Hasebe T, Endoh Y, et al. In vivo characterization of bone marrow-derived fibroblasts recruited into fibrotic lesions. Stem Cells. 2005;23:699–706. 79. Deng W, Han Q, Liao L, Li C, Ge W, Zhao Z, et al. Engrafted bone marrow-derived fik–(1 ⫹ ) mesenchymal stem cells regenerate skin tissue. Tissue Eng. 2005;11:110–19. 80. Mori L, Bellini A, Stacey MA, Schmidt M, Mattoli S. Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow. Exp Cell Res. 2005;304:81–90. 81. Gillitzer R, Goebeler M. Chemokines in cutaneous wound healing. J Leukoc Biol. 2001;69:513–21. 82. Kolf CM, Cho E, Tuan RS. Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation. Arthritis Res Ther. 2007;9:204. 83. Fu X, Li H. Mesenchymal stem cells and skin wound repair and regeneration: possibilities and questions. Cell Tissue Res. 2009;335:317–21. 84. Fathke C, Wilson L, Hutter J, Kapoor V, Smith A, Hocking A, et al. Contribution of bone marrow-derived cells to skin: collagen deposition and wound repair. Stem Cells. 2004;22:812–22. 85. Kim WS, Park BS, Sung JH, Yang JM, Park SB, Kwak SJ, et al. Wound healing effect of adipose-derived stem cells: a critical role of secretory factors on human dermal fibroblasts. J Dermatol Sci. 2007;48:15–24. 86. Branski LK, Gauglitz GG, Herndon DN, Jeschke MG. A review of gene and stem cell therapy in cutaneous wound healing. Burns. 2009;35:171–8. 87. Rossiter H, Barresi C, Pammer J, Rendl M, Haigh J, Wagner EF, et al. Loss of vascular endothelial growth factor a activity in murine epidermal keratinocytes delays wound healing and inhibits tumor formation. Cancer Res. 2004;64:3508–16. 88. Deodato B, Arsic N, Zentilin L, Galeano M, Santoro D, Torre V, et al. Recombinant AAV vector encoding human VEGF165 enhances wound healing. Gene Ther. 2002;9: 777–85. 89. Ebrahimian TG, Pouzoulet F, Squiban C, Buard V, André M, Cousin B, et al. Cell therapy based on adipose tissuederived stromal cells promotes physiological and pathological wound healing. Arterioscler Thromb Vasc Biol. 2009;29:503–10.
90. Medina A, Scott PG, Ghahary A, Tredget EE. Pathophysiology of chronic nonhealing wounds. J Burn Care Rehabil. 2005;26:306–19. 91. Smiell JM, Wieman TJ, Steed DL, Perry BH, Sampson AR, Schwab BH. Efficacy and safety of becaplermin (recombinant human platelet-derived growth factor-BB) in patients with nonhealing, lower extremity diabetic ulcers: a combined analysis of four randomized studies. Wound Repair Regen. 1998;7:335–46. 92. Lynch SE, Nixon JC, Colvin RB, Antoniades HN. Role of platelet-derived growth factor in wound healing: synergistic effects with other growth factors. Proc Natl Acad Sci USA. 1987;84:7696–700. 93. Marston WA, Hanft J, Norwood P, Pollak R, Dermagraft Diabetic Foot Ulcer Study Group. The efficacy and safety of dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care. 2003;26:1701–5. 94. Cross K, Mustoe T. Growth factors in wound healing. Surg Clin North Am. 2003;83:531–45. 95. Blanton MW, Hadad I, Johnstone BH, Mund JA, Rogers PI, Eppley BL, et al. Adipose stromal cells and plateletrich plasma therapies synergistically increase revascularization during wound healing. Plast Reconstr Surg. 2009;123:56S–64S. 96. Ravari H, Hamidi-Almadari D, Salimifar M, Bonakdaran S, Parizadeh MR, Koliakos G. Treatment of non-healing wounds with autologous bone marrow cells, platelets, fibrin glue and collagen matrix. Cytotherapy. 2011;13: 705–11. 97. García-Olmo D, García-Arranz M, Herreros D, Pascual I, Peiro C, Rodríguez-Montes JA. A phase I clinical trial of the treatment of Crohn’s fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum. 2005;48: 1416–23. 98. García-Olmo D, Herreros D, Pascual I, Pascual JA, Del-Valle E, Zorrilla J, et al. Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum. 2009;52:79–86. 99. García-Arranz M, Gómez-Pinedo U, Hardisson D, Herreros D, Guadalajara H, García-Gómez I, et al. Histopathological analysis of human specimens removed from the injection area of expanded adipose-derived stem cells. Histopathology. 2010;56:979–82. 100. Varma MJ, Breuls RG, Schouten TE, Jurgens WJ, Bontkes HJ, Schuurhuis GJ, et al. Phenotypical and functional characterization of freshly isolated adipose tissue-derived stem cells. Stem Cells Dev. 2007;16:91–104. 101. Wagner W, Wein F, Seckinger A, Frankhauser M, Wirkner U, Krause U, et al. Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Exp Hematol. 2005;33:1402–16. 102. Oedayrajsingh-Varma MJ, van Ham SM, Knippenberg M, Helder MN, Klein-Nulend J, Schouten TE, et al. Adipose tissue-derived mesenchymal stem cell yield and growth characteristics are affected by the tissue-harvesting procedure. Cytotherapy. 2006;8:166–77. 103. Festy F, Hoareau L, Bes-Houtmann S, Pequin AM, Gonthier MP, Munstun A, et al. Surface protein expression between human adipose tissue-derived stromal cells and mature adipocytes. Histochem Cell Biol. 2005;124:113–21. 104. Dicker A, Le Blanc K, Âström G, van Harmelen V, Götherström C, Blomqvist L, et al. Functional studies of mesenchymal stem cells derived from adult human adipose tissue. Exp Cell Res. 2005;308:283–90.
Fibrin glue as the cell-delivery vehicle for mesenchymal stromal cells in regenerative medicine
XIUWEN WU, JIANAN REN & JIESHOU LI
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Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China Abstract The use of tissue-engineering techniques such as stem-cell therapy to renew injured tissues is a promising strategy in regenerative medicine. As a cell-delivery vehicle, fibrin glues (FG) facilitate cell attachment, growth and differentiation and, ultimately, tissue formation and organization by its three-dimensional structure. Numerous studies have provided evidence that stromal cells derived from bone marrow (bone marrow stromal cells; BMSC) and adipose tissue (adiposederived stromal cells; ADSC) contain a population of adult multipotent mesenchymal stromal cells (MSC) and endothelial progenitor cells that can differentiate into several lineages. By combining MSC with FG, the implantation could take advantage of the mutual benefits. Researchers and physicians have pinned their hopes on stem cells for developing novel approaches in regenerative medicine. This review focuses on the therapeutic potential of MSC with FG in bone defect reconstruction, cartilage and tendon injury repair, ligament, heart and nerve regeneration, and, furthermore, wound healing. Key Words: adipose-derived stromal cells, bone-marrow derived stromal cells, fibrin glues, mesenchymal stromal cells, regenerative medicine
Introduction Regenerative medicine is an alternative approach for replacing or regenerating tissue damage and organ loss. The strategies that promote tissue regeneration, instead of damaged tissue substitution, are usually based on the use of tissue-engineering techniques. The tissue-engineering approach in this review, which combines stem cells and fibrin glue (FG), provides a biocompatible scaffold material for the renewing cell sources. Stem cells are characterized by the ability to differentiate into many lineage-specific cell types. With the development of two of the technologies that allow the isolation of stem cells, monoclonal antibodies and high-speed sorting of cells, stem cells are currently major cell sources in tissue engineering (1). Despite the pluripotency of embryonic fetal stem cells, research has been driven toward adult stem cells for use in tissue repair and regeneration, because of ethical, regulatory and availability concerns (2).
Several organs and tissues, such as skin (3), blood vessels (4), brain (5), skeletal muscle (6), liver (5), testis (7) and pancreas (5), have shown the existence of adult stem cells. Among the many available sources, mesenchymal stromal cells (MSC) derived from bone marrow or adipose tissue are commonly used as multipotent autologous cell sources and can be collected through relatively non-invasive methods (5). Among MSC, bone marrow stromal cells (BMSC) have been considered the major source for many years in the field of tissue engineering (2). However, because of the ease of harvest and abundance, adipose-derived stromal cells (ADSC) are also regarded as attractive, readily available adult stem cells, and have become increasingly popular for use in many applications (2).
Characterization of MSC MSC are identified through a combination of physical, phenotypic and functional properties (8):
Correspondence: Jianan Ren, Department of Surgery, Jinling Hospital, Medical School of Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, PR China. E-mail: [email protected] (Received 1 September 2011; accepted 3 November 2011) ISSN 1465-3249 print/ISSN 1477-2566 online © 2012 Informa Healthcare DOI: 10.3109/14653249.2011.638914
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(a) adherence to plastic; (b) specific surface antigen expression; (c) multipotent differentiation potential to diverse lineages such as osteoblasts, adipocytes, chondroblasts, cartilage, muscle and neuronal-like cells. Surface antigen expression has been used extensively in immunology. Typical categories of surface marker proteins expressed in MSC include: adhesion molecules such as integrins (CD29, CD49e), receptor molecules such as hyaluronate (CD44), cadherins (CD144), surface enzymes (CD73), extracellular matrix proteins (CD90, CD105), intercellular adhesion molecules (CD54), vascular adhesion molecules (CD106), complement regulatory proteins, and histocompatibility antigens (9). MSC may be typically negative for CD45, CD34, CD31 and CD14, and positive for CD13, CD29, CD44, CD49e, CD54, CD55, CD63, CD73, CD90, CD105, CD106, CD144, CD146, CD166 and human leukocyte antigen (HLA). This phenotype is valid for both human and murine cells, with the exception of CD34, which may be positive in some murine MSC samples and may be positive very early in human cultures but very rapidly lost (10). The cluster of differentiation
(CD) marker list of ADSC and BMSC is shown in Table I. FG as the cell-delivery vehicle Adult stem cells require an appropriate scaffold to facilitate cell attachment, growth and differentiation, and, ultimately, tissue formation and organization. The presence and properties of these scaffolds, which are primarily hydrogels such as FG (11–13) and platelet-rich gels (14), can greatly influence cell survival and differentiation. Stacey et al. (15) observed a markedly decreased differentiation in two-dimensional (2-D) cultures compared with three-dimensional (3-D) scaffolds. Among 3-D scaffolds, including platelet-poor plasma, alginate, fibrin gel and collagen sponge, fibrin gel showed an optimal combination of mechanical characteristics and support of MSC differentiation and angiogenic factor secretion (16). The use of FG was advocated in tissue engineering for its 3-D characteristics, providing appropriate cells with contact with the culture environment through their surfaces.
Table I. Cell marker list of ADSC, BMSC and mouse ADSC or BMSC.
Positive markers
Negative markers
Surface marker
ADSC (9,100–104) Human
BMSC (82,101,103,104) Human
ADSC or BMSC (82) Mouse
CD13 CD29 CD44 CD49e CD54 CD55 CD63 CD73 CD90 CD105 CD106 CD144 CD146 CD166 HLA-ABC CD11b CD14 CD19 CD31 CD34 CD45 Stro-1 CD3 CD117 CD62L CD95L
⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ − ⫹ ⫹ ⫹ ⫹ − − − ⫹ /− ⫹/− − ⫹/− − − − −
⫹ ⫹ ⫹/− ⫹ ⫹ ⫹ ⫹ ⫹ ⫹/− ⫹ ⫹/− ⫹ ⫹ ⫹ ⫹
⫹/− ⫹ ⫹/−
–
⫹/−
− ⫹/− − ⫹/− − − − −
− ⫹/− −
⫹/− ⫹ ⫹
−
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Implantation of MSC with fibrin glue carriers In addition to the 3-D structures, FG combine some important advantages such as high seeding efficiency, uniform cell distribution (17) and adhesion capabilities (18). FG is non-cytotoxic, and is a naturally porous physiologic scaffold that can stimulate cell adhesion and growth (19,20). Furthermore, when produced from the patient’s own blood, it could be used as an autologous scaffold without the potential risk of foreign body reaction or infection (21). Consisting of component I (fibrinogen and factor XIII) and component II (thrombin and calcium chloride), FG mimics the final stages of blood coagulation. Currently commercial allogeneic fibrin sealants are in clinical use, particularly for those patients whose clinical condition contraindicates an autologous procedure. Because of continued concerns over the cost and safety of commercial preparations, home-made FG are still attractive in spite of their low concentrations of fibrinogen. Concentrated fibrinogen could be obtained from a single unit of plasma by several methods, including cryoprecipitation, ammonium sulfate solution, ethanol precipitation and ethylene glycol precipitation (22). Cryoprecipitation can be performed with different freeze–thaw cycles; it is time-consuming but does not require the addition of exogenous chemicals. Although chemical precipitations result in a rapid procedure and high bond strength (23), the purity of the final product is a concern (24). Entirely autologous FG usually use thrombin produced from human plasma, rather than bovine origin, in order to avoid the possible formation of antibodies, which cross-react with the patient’s coagulation factor (25). Clinical applications A number of studies have demonstrated the advantages of using MSC for the repair and regeneration of multiple tissue types (26–33). FG in combination with an appropriate MSC source has been used in a variety of tissue-engineering applications, including bone defect reconstruction, cartilage and tendon injury repair, and ligament, heart and nerve regeneration. In addition, FG has been used to promote the healing of severe burns and chronic wounds. Furthermore, FG combined with ADSC is under clinical trials for chronic intestinal fistulae, including Crohn’s disease-related fistulae. Orthopedics Bone substitutes Fibrin sealants have provided the angiogenic basis of a composite graft to bone tissue and initial differentiation site for undifferentiated cells (34,35). Several authors have demonstrated that a fibrin matrix is
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an optimal support for transplanted MSC to obtain osseous defect regeneration. The ideal bone substitute should be biocompatible, biodegradable at the expense of bone growth, and moldable, with sufficient mechanical properties to fill and restore bone defects (36). As a biologic scaffold, however, FG has two major disadvantages: rapid degradation and low mechanical strength. To solve the first problem fibrinolytic inhibitor can be added, preventing the lysis of clots. One way to deal with the second problem is to elevate the concentration of fibrinogen, which is decided by the concentration of fibrinogen in the blood. Another way is to combine bioceramics with fibrin sealant, resulting in accumulated properties. The physical, chemical and biologic properties of both bioceramics and FG may be combined for preparing advanced bone substitutes (19). The association of bioceramics, fibrin sealants and stem cells may develop the clinical applications of bone substitutes. An in vitro study from Leong et al. (37) substantiated the potential of ADSC as a source of osteogenically capable progenitor cells in a 3-D fibrin/collagen matrix. Cui et al. (38) found that the calcium phosphate cement–FG composite supported BMSC attachment and proliferation. Several studies with experimental animals have demonstrated that fibrin sealants can provide a good scaffold containing numerous growth factors for proliferation of osteoinduced BMSC (39,40). Ito et al. (39) showed an increase in bone regeneration in a canine mandibular defect using MSC–platelet-rich plasma (PRP)–FG hybrid constructs, compared with MSC–FG constructs alone after 4 and 8 weeks. A combination of autologous platelet-rich FG (PRFG) with BMSC and MEDPOR (Porex Medical, Fairburn, GA, USA) as guided tissue regeneration could act as an osteogenic substitute (40). Tendon and ligament repair As well as bone substitutes, the use of autologous BMSC to repair experimental injuries of tendons and ligaments has been described amply in experimental animals (41,42). In 2003, Smith et al. (43) suggested for the first time the use of autologous mesenchymal cells obtained from bone marrow in spontaneous tendon lesions in horses. It was postulated that the biomechanical properties and histologic appearances of injured tissues were improved because of MSCmediated repair (41,44,45). A preliminary study from Lacitignola et al. (46) demonstrated that BMSC implantation combined with FG results in an effective clinical and ultrasound healing for tendon injury. Crovace et al. (47) described for the first time the efficacy of bone
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marrow-derived mononuclear cell (BMMNC) suspended in FG in an equine model of experimental tendinitis. The use of BMMNC is a simpler and more cost-e ective method than the use of cultured BMSC, thus resulting in its significant role in the future of tendon injury treatment.
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Cartilage reconstruction Human articular cartilage has limited repair potential (48). With the application of tissue-engineered cartilage, numerous pre-clinical studies have reported the development of hyaline-like tissue from autologous culture-expanded BMSC (49,50), and some have shown superior functionality of BMSC over chondrocytes (51,52). All these results have pushed MSC-based cartilage repair into clinical trials. Several clinical trials have reported the use of BMSC in articular cartilage defects (53–56). Haleem et al. (57) demonstrated that patients with osteochondral defects that were reconstructed with BMSC with a PRFG carrier experienced significant improvement in their functional knee scores and magnetic resonance imaging (MRI) findings as early as 6 months and maintained over 12 months post-operatively. Dragoo et al. (58) found that implanted ADSC developed the early functional characteristics of native hyaline cartilage in animal models, demonstrating themselves as promising cells for autologous cartilage regeneration. Cardiac functions Cardiac tissue engineering may provide an alternative treatment rather than replacing the damaged tissue. FG has several advantages as a cell scaffold for cardiovascular tissue engineering, such as a high seeding efficiency and uniform cell distribution (59). Furthermore, FG can be modified to facilitate its functionality in the myocardium (60–62). Christman et al. (63) stated that injection of FG alone could preserve infarct wall thickness and cardiac function. Angiogenesis is thought to salvage at-risk cardiomyocytes and enhance the survival of donor stem cells by improving the blood circulation in the infarction regions. Providing a suitable matrix environment for endothelial cell migration and branching morphogenesis (64), fibrin improves the microenvironment by inducing angiogenesis. In recent research by Guo et al. (59), heart function was significantly improved in rats receiving BMSC with FG, compared with BMSC transplantation alone and FG transplantation alone. Besides the enhancement of angiogenesis, FG gave the cells a temporary semirigid scaffold after transplantation, protecting BMSC resistance to hypoxia. All these cytoprotective effects
of FG are beneficial for the survival and differentiation of BMSC. Zhang et al. (65) transplanted ADSC combined with FG in rat infraction models and reported that the heart function improved significantly in the fibrin ⫹ ADSC group. This is the first study that has been devoted to demonstrating the therapeutic potential of ADSC and FG in the management of myocardial infarction. Nerve regeneration FG seeded with regenerative cells could be constructed as a bioresorbable nerve, which could guide regenerating axons without inhibiting the process of growth and maturation (66). With good tissue acceptance and a porous structure, the fibrin conduit allows neurotrophic growth factors to penetrate into the lumen. The degradation of the fibrin within 4 weeks also avoids compression syndromes and enhances biocompatibility (13). Recently, it has been shown that autologous FG is beneficial for peripheral nerve regeneration in an experimental rabbit model (67). Kalbermatten et al. (68) also used fibrin as a new nerve guide and bridged nerve defects. All these studies suggest a clinically interesting role for the new fibrin conduit during the initial phase of peripheral nerve regeneration. This application of ADSC and BMSC in promoting peripheral nerve regeneration is promising. In vivo research has demonstrated that MSC can be differentiated into cells that are Schwann cell-like, and can physically engraft and myelineate regenerating axons, thus enhancing nerve regeneration (69–71). Stem cells could also improve regeneration with the release of soluble nerve growth factors such as brain-derived neurotrophic factor (72) and angiogenic molecules, including vascular endothelial growth factor (VEGF) (73). Promising results have been achieved with the combination of regenerative cells and fibrin conduit, which are hopeful steps toward future clinical applications in the case of peripheral nerve injury. di Summa et al. (74) found that fibrin seeded with Schwann cells differentiated from ADSC-enhanced axonal regeneration. Wound repair Angiogenesis, immunity and epithelial cover are the three keys to healing and soft tissue maturation (75). It has been demonstrated clearly that fibrin matrix leads directly to angiogenesis (76), constitutes a natural support to immunity, and guides the coverage of injured tissues (75), featuring all the necessary parameters permitting optimal healing.
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Implantation of MSC with fibrin glue carriers The ability of stem cells to promote angiogenesis, secrete growth factors and differentiate into multiple cell types, may provide their role in promoting wound repair when combined with fibrin matrix (77). It has been demonstrated that BMSC are progenitors of wound-healing cells, such as fibroblasts (78), keratinocytes (79) and fibrocytes (80), which produce cytokines and orchestrate a cascade of events (81– 83). In addition, BMSC influences the structure of scar tissue for its secretion of collagen type III. Collagen type III may be secreted by BMSC (84), which is elevated to a ratio of 1:2 to collagen type I during the wound-healing process. Both ADSC and BMSC can accelerate the reepithelization of cutaneous wounds (12,85,86). Direct cell-to-cell contact and secretory-induced paracrine activation may be the two ways that ADSC promotes human dermal fibroblast proliferation (85,86). As a critical regulator of angiogenesis in wound healing (87,88), VEGF has a positive effect on wound repair. Ebrahimian et al. (89) also stated that ADSC has the potential to differentiate into keratinocytes, and to produce keratinocyte growth factor (KGF) as well as VEGF. Chronic wounds Chronic wounds include venous ulcers, pressure ulcers and diabetic ulcers (90), which present a major challenge in modern medicine. An innovative approach that delivers growth factors, such as plateletderived growth factor (91), insulin like growth factor-I (92) and fibroblasts (93), has been developed in the last few years. However, only limited success has been demonstrated in studies using these growth factors (94). On the other hand, several studies have evaluated the potential therapeutic effects of MSC on wound healing. The fibrin matrix, which provides a scaffold for the ADSC, permits improvement in the timing of chronic wound healing (95). Full-thickness skin defect wounds of pigs were achieved by local implantation of ADSC. Falanga et al. (12) showed complete closure of human chronic wounds after 7 weeks with a fibrin spray delivery of BMSC. In recent years, the combination of BMSC and PRFG has been demonstrated to synergize chronic wound healing in patients with diabetic wounds, taking advantage of the mutual benefits (96). An increase in tissue vascularization was reported in each of these cases and was thought to be an important component of the activity. Intestinal fistulae The application of ADSC along with FG in the healing of chronic fistulae from Crohn’s disease was
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the first phase I clinical trial of ADSC therapy (97). Cultured for between 6 and 31 days, ADSC was inoculated in four patients with nine fistulae. Seventyfive per cent of the fistulae (6/8) showed complete healing within 8 weeks of follow-up. After promising results with a phase I trial of treatment of perianal complex fistulae with ADSC, a phase II clinical trial evaluated the safety and efficacy of this novel therapy. The proportion of patients with fistulae healing was significantly higher for ADSC (71%), recurrences in the first year were rare and no treatment-associated adverse effects were reported (98). Subsequent histologic and electron microscopic results showed fistulae healing at the implanted areas; what was more, there were no signs of rejection or presence of tumor cells or neoplastic processes, regarding the safety of this innovative therapy (99). Conclusions In conclusion, it is likely that BMSC and ADSC with fibrin scaffolds will have extensive applications in the future. However, a number of challenges still remain before the therapy can be used in everyday clinical practice. A greater understanding of the mechanisms of interaction among MSC, growth factors and fibrin matrix regarding tissue regeneration is needed to advance the clinical utility of this therapy. Given that the potential risks of applying stem cells, additional studies are required on the safety of clinical tissue regeneration. Acknowledgments This work was supported by a grant from Climb Program in Natural Science Foundation for Distinguished Scholars, Jiangsu, China (BK2010017). Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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