Rescue plan for Achilles: Therapeutics steering the fate and functions of stem cells in tendon wound healing

Rescue plan for Achilles: Therapeutics steering the fate and functions of stem cells in tendon wound healing Magdalena Schneider a , Peter Angele a ,TeroA.H.Järvinen b , Denitsa Docheva a, ⁎ a Experimental Trauma Surgery, Department of Trauma Surgery, University Medical Centre Regensburg, Regensburg, Germany b Faculty of Medicine and Life Sciences & Department of Orthopedics, Unit of Musculoskeletal Surgery, University of Tampere and Tampere University Hospital, Tampere, Finland abstractarticle info Article history: Received 3 September 2017 Received in revised form 1 December 2017 Accepted 22 December 2017 Available online 24 December 2017 Due to the increasing age of our society and a rise in engagement of young people in extreme and/or competitive sports, both tendinopathies and tendon ruptures present a clinical and financial challenge. Tendon has limited natural healing capacity and often responds poorly to treatments, hence it requires prolonged rehabilitation in most cases. Till today, none of the therapeutic options has provided successful long-term solutions, meaning that repaired tendons do not recover their complete strength and functionality. Our understanding of tendon biology and healing increases only slowly and the development of new treatment options is insufficient. In this review, following discussion on tendon structure, healing and the clinical relevance of tendon injury, we aim to elucidate the role of stem cells in tendon healing and discuss new possibilities to enhance stem cell treatment of injured tendon. To date, studies mainly apply stem cells, often in combination with scaffolds or growth factors, to surgically created tendon defects. Deeper understanding of how stem cells and vasculature in the healing tendon react to growth factors, common drugs used to treat injured tendons and promising cellular boosters could help to develop new and more efficient ways to manage tendon injuries. © 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). Keywords: Tendon Tendon repair, growth factors Mesenchymal stem cells Bone marrow derived mesenchymal stem cells Adipose tissue derived mesenchymal stem cells Perivascular cells Tendon-derived cells Tendon stem/progenitor cells Tendon vasculature Cellular boosters 1. Introduction In Greek mythology, Achilles, the demigod hero, is almost invulnerable except for his Achilles heel, whose injury resulted in his death. How could a tendon injury take such a prominent place in Greek mythology? This injury was obviously such a crucial and inexplicable event that it was extensively honored in the legendary Iliad of Homer. Presumably, the ancient Greeks have already wondered how it can happen that even in young powerful athletes the biggest tendon of man can suddenly break. Even today, we cannot explain or foresee when and why this greatest chord of man tears. Nor can we offer with great degree of certainty, especially in elderly individuals, complete reconstitution to normal strength and function of the tendon tissue once it has been ruptured. As an integral part of the musculoskeletal system, tendons connect and transmit forces from muscle to bone. As a result of their composition and structure they are able to store elastic energy and withstand the high tensile forces that enable locomotion [1]. With an aging population and an increase in sports participation the risk for tendinopathy or tendon ruptures grows steadily. Approximately 45% of musculoskeletal injuries in the US are tendon or ligament injuries [2].Tendoninjuries are most common in the rotator cuff, the Achilles tendon and the patellar tendon [3] and the pathologies are often based on a degenerative process. Extensor and flexor tendons of the hand are also often subjected to direct lacerations in patients of all ages [2,3]. This review article aims to: (1) provide background information on tendon structure and the lengthy and insufficient healing process of tendon after injury including the clinical relevance; (2) highlight the influence of different types of mesenchymal stem cells on tendon healing; (3) summarize how different growth factors involved in tendon healing influence mesenchymal stem cells (MSCs) and their capability to Advanced Drug Delivery Reviews 129 (2018) 352–375 Abbreviations: ADMSC, Adipose tissue derived mesenchymal stem cells; bFGF, Basic fibroblast growth factor; Bgn, Biglycan; BM, Bone marrow; BMMSC, Bone marrow derived mesenchymal stem cells; BMP, Bone morphogenetic protein; Col, Collagen; COMP, Cartilage oligomeric matrix protein; CTGF, Connective tissue growth factor; Dcn, Decorin; ECM, Extracellular matrix; El, Elastin; ESFTT, Engineered scaffold free tendon tissue; ETM, Engineered tendon matrix; Fn, Fibronectin; Fmod, Fibromodulin; GDF, Growth and differentiation factors; GFP, Green fluorescent protein; GNT, Glyceryl trinitrate; HB-EGF, Heparin binding endothelial growth factor; IGF-1, Insulin-like growth factor-1; Il, Interleukin; INF, Interferon; Lum, Lumican; MMP, Matrix metalloproteinase; MRI, Magnetic resonance imaging; MSC, Mesenchymal stem cells; NO, Nitric oxide; PC, Perivascular cell; PDGF, Platelet-derived growth factor; PEG, Polyethylene glycol; PRP, Platelet rich plasma; Scx, Scleraxis; SFDLT, Superficial flexor digitorum longus tendon; SMA, Smooth muscle actin alpha; SMC, Smoot muscle cells; TGFβ, Transforming growth factor beta; TN-C, Tenascin C; TNF, Tumor necrosis factor; Tnmd, Tenomodulin; TSPC, Tendon stem/progenitor cells; VEGF, Vascular endothelial growth factor. ⁎Corresponding author at: Experimental Trauma Surgery, Department of Trauma Surgery, University Regensburg Medical Centre, Franz-Josef-Strauss-Allee 11, Regensburg, Germany. E-mail address: [email protected] (D. Docheva). https://doi.org/10.1016/j.addr.2017.12.016 0169-409X/© 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr enhance tendon healing; (4) clarify the effects of commonly used drugs on tendon-specific stem/progenitor cells and vasculature of the tendon and; (5) discuss the possibility of cellular boosters to amplify the positive effects of mesenchymal stem cells on tendon healing. In vivo and in vitro studies have been analyzed and summarized. 1.1. Tendon structure Tendons are a hierarchically structured dense connective tissues (Fig. 1), designed to transmit forces between muscle and bone. They are mainly composed of collagen fibers and tenocytes that lie embedded in a well-ordered extra cellular matrix (ECM), containing high amounts of proteoglycans. The main purpose of the collagen fibers is to resist tension, while the proteoglycans provide the viscoelastic properties for the tendon. Cross-linked tropocollagen form insoluble collagen molecules, and aggregate into microfibrils. These microfibrils combined to form fibrils that group together into fibers aligning from end to end within the tendon. Fibers group together into a bundle that is ensheathed by a thin layer of loose connective tissue, known as the endotenon. In addition to binding the fibers together, the endotenon enables fiber groups to glide over each other and carries blood vessels, nerves and lymphatics to deeper portions of the tendon [1,4,5]. Fascicles are groups of fiber bundles ensheathed by endotenon. The epitenon, a dense fibrillary network of collagen, binds fascicles together to create the tendon [5].Thiscomplex internal ultrastructure leads to high tensile force and resilience but also prevents damage and the separation of fibers under mechanical stress [6]. The collagen network of the tendon matrix forms a regular sinusoidal pattern called “crimps”, which act as a buffer or a shock absorber within the tendon, permitting small longitudinal elongation of individual fibrils without permanent damage to the tissue [7]. It has been estimated that these crimps allow 1–3% stretching of the tendon tissue, and thus, provide a highly efficient “safety measure”for tendons to resist sudden, possibly hazardous tensile strains subjected on them by excessive contraction or elongation of the attached skeletal muscle [7]. 65–80% of the dry mass of tendon consists of collagen, with collagen I (Col I), accounting for up to 95% of the total collagen, while only 1–2% consist of elastin (El) [4,8–10]. Besides Col I, the tendon also contains collagen III (Col III), restricted to the tendon sheets in healthy tendons [6,11], as well as small amounts of Col V, VI, XII, XIV and XV [6,12]. Together with collagen crimps, elastic fibers made out of El and tenascin-C (TN-C) in the tendon provide extensibility and flexibility for the tissue and permit long-range deformability as well as passive recoil without energy input [13]. The ground substance in tendons is built up by proteoglycans like decorin (Dcn), biglycan (Bgn), fibromodulin (Fmod) and lumican (Lum), glycoproteins, El and inorganic molecules (copper, manganese and calcium) [14]. 60 to 80% of the total weight of the ground substance is water, leading to a hydrophilic, gel-like texture. The water binding capacity of the ground substance improves the elasticity of the tendon, making it more resistant against shear and compressive forces, and provides support to the collagen fibers [5]. Tenocytes and tenoblasts are approximately 90–95% of tendon cells. Tenocytes, being terminally differentiated, are spindle-shaped, with elongated nuclei and thin cytoplasmic protrusions anchoring the collagen fibers, while tenoblasts are more roundly shaped with a large, ovoid nucleus [15]. The discrimination between tenocytes and tenoblasts is based on cell shape appearance and it is still lackingprecise molecular separation via marker gene expression. Therefore, the exact tendon cell differentiation process is not fully understood and lagging far behind the other musculoskeletal lineages. In recent years, several research papers based on knockout or reporter mouse models have Fig. 1. A schematic drawing of tendon structure and the localization of tenocytes and TSPCs. The tendon is hierarchically structured in fascicles, fibers and fibrils, composed of collagen molecules. Despite tenocytes, tendons contain a pool of stem and progenitor cells. The exact location of these TSPCs is not clarified yet and therefore indicated with question mark. Locations discussed for different types of stem/progenitor cells in the tendon are the epitenon (TSPC type 1), the endotenon (TSPC type 2) and the perivascular region. 353M. Schneider et al. / Advanced Drug Delivery Reviews 129 (2018) 352–375 aimed to identify critical genes for tendon formation or maturation [16]. Despite some advancement in recapitulating the discrete molecular steps of the tenogenic differentiation cascade, the field is in need of identifying specific surface markers which will allow sorting of tendon cell populationsand in turn will aid in better characterization of the tendon regional cell niches. The remaining 5–10% of cells in tendon is composed of chondrocytes, synovial cells of the tendon sheath, capillary endothelial cells and smooth muscle cells of arterioles. Tendon cells engage in energy production via the Krebs' cycle, anaerobic glycolysis and the pentose phosphate shunt as well as in the biosynthesis of collagens and all additional components of the tendon matrix [1,10,17]. According to the most recent data, most of the tendon ECM is produced right after birth, thereafter very little ECM production takes place over the life span of an individual [18].With age, aerobic energy production and synthesis of ECM components decreases. The shift to anaerobic energy production leads to the ability to tolerate low oxygen levels, reducing the risk of ischemia and necrosis during extended periods of stress but also results in a poor and slow healing capacity [5]. 1.2. Tendon healing The exact mechanisms of tendon healing are still not completely understood, due to low number of detailed biochemical, histopathological and biomechanical studies as well as species-related differences in the healing process. Most insight has been gained from the analysis of animal models of experimentally induced tendon rupture [19,20],orbyanalyzing human ruptured tendons, but since these are models of acute injury only, they do not help in understanding the healing process in tendinopathy [21]. Currently, an optimal experimental model of tendinopathy is not available for two main reasons. Firstly, due to poor understanding of the pathogenesis of tendinopathy and especially of tendinosis and second, as there is no animal with exactly the same features of human tendons, no one species represents a gold standard [20]. From a translational point of view, non-human primates represent the most ideal species as they are the closes to humans in terms of tendon anatomy and physiology but their use is limited due to ethical considerations as well as high costs [20]. Small species such as rodents are the most common animal models. However, their tendons are better suited to withstand some types of stress such as exposing their extremities to excessive running or hill work (steep inclination or declination on treadmill), which leads to no significant structural changes in certain tendons [20]. When treated chemically, by injections of collagenase, corticosteroids or cytokines, the rodent tendons either do not induce pathology that replicates the human condition or over-respond by intense inflammation followed by progressive tendon reparation [20]. It is agreed that during the course of healing, a tendon passes through three main stages (Table 1 and graphical abstract), which may overlap, and that their duration depends on location and severity of the defect [14,22,23]. In the inflammation stage, starting directly after injury and lasting approximately for 3 days, the blood clot, created by the tear that also ruptures blood vessels, serves as a preliminary scaffold for invading cells. It then activates the release of chemoattractants from activated platelets, which initiate the migration of inflammatory cells, such as neutrophils and monocytes, from circulation to the injury site. Monocytes differentiate into macrophages, which digest necrotic material via phagocytosis and an increase of vasoactive and chemotactic factors results in the recruitment and activation of tenocytes [22,24,25]. During this stage, the formation of a vascular network by sprouting angiogenesis is initiated, which is essential for the survival of tenocytes engaged in the synthesis of the new fibrous tissue [26]. The newly formed tissue mainly consists of fibronectin and Col III, produced by tenocytes at the injury site [27]. The second proliferation stage lasts up to a few weeks. During this phase, macrophages release growth factors to direct cell recruitment and activity [25]. Thereafter, tendon fibroblasts from the epitenon and the synovial sheath and intrinsic tenocytes from the endotenon are recruited to the injury site to produce Col III, fibronectin and ECM components (e.g. proteoglycans) to create an initially unorganized ECM [28, 29]. Then the production of Col III commences and it is replaced by substantially stronger Col I. Typical features of the proliferation stage are high cellularity and water absorption. Following 6–8 weeks, the remodeling stage commences and takes about 1–2 years, depending upon age and condition of the patient. This stage can be subdivided into the consolidation stage and the maturation stage. The consolidation stage lasts up to 10 weeks and is characterized by tissue changes from a highly cellular to a more fibrous appearance. Metabolism of tenocytes is still high in this phase and the tenocytes and collagen fibers start to align in the direction of stress to restore tensile strength and tendon stiffness. Furthermore, the synthesis of Col III is replaced by the synthesis of Col I. Tendon fibroblasts transform to myofibroblast, which contract the large granulation tissue into substantially smaller, permanent scar tissue. The final maturation stage can take 1–2 years during which a change from fibrous tissue to a scar-like tendon tissue can be observed. During the course of this stage, tenocytes metabolism and tendon vascularity decrease [21]. Two different mechanisms, that are most likely acting conjointly, have been suggested for tendon healing. The extrinsic healing theory states that fibroblasts and inflammatory cells from the periphery and the blood vessels migrate to the injury site to proliferate and form adhesions. Extrinsic healing is believed to take place mostly in the early phases of healing. Then intrinsic healing takes over, meaning that cells Table 1 Phases of tendon healing and growth factors involved. Repair phase Growth factors involved Effects References Inflammatory IGF-1 PDGF TGF-β VEGF bFGF Invasion of inflammatory cells and fibroblasts Chemo attraction, stimulation and proliferation of macrophages and fibroblasts, expression of growth factors Chemoattraction, cell migration and proliferation Angiogenesis, increase in capillary permeability Cell proliferation [253–258] [259–262] [135,137,258,260,263,264] [235,265,266] [133,135,178] Proliferative IGF-1 PDGF TGF-β GDF Stimulation of migration, division and ECM expression of tenocytes Stimulation of division, proliferation and ECM expression of tenocytes Cell migration and ECM production Collagen and GAG production, Cell proliferation and realignment [267,268] [260,268] [137,148,258] [94,263,269–272] Remodeling IGF-1 TGF-β GDF ECM remodeling Collagen synthesis, myofibroblasts, scar formation Collagen synthesis [258] [161,162,258,263,264] [94,263,269–272] 354 M. Schneider et al. / Advanced Drug Delivery Reviews 129 (2018) 352–375 from the endotenon are activated and migrate to the injury site, where they proliferate, produce and reorganize ECM and give support to the newly built vascular network [21,29]. There is only very little evidence on the origin of the participating cells. One study states that initially circulating cells (e.g. from bone marrow) invade the injury site and are then followed by activated local cells, which participate in the proliferative and remodeling phase, also confirming the biphasic model of tendon healing described above [30]. Various growth factors are involved in the activation and concertation of cellular processes during the different phases of tendon healing (Table 1 and graphical abstract) [21,29,31]. The release of growth factors is triggered first from the activated platelets straight after injury. Furthermore, all tissuescontain growth factors in their inactive form and these inactive, “in storage”growth factors are activated in response to injury. Together, these growth factors initiate the inflammatory cascade and recruit more inflammatory cells to the site of injury within hours [24,25,31].Theinflammatory cells, in turn, secrete plenty of growth factors and amplify the inflammatory cascade [24,25,31]. The tendon cells located next to the injury site area are also activated and can produce growth factors, and mechanical loading placed on the injured tendon can further induce the production of growth factors [24,25,31]. The exact effect of these growth factors on stem cells in tendon healing will be discussed in Section 2 of this review. The healing ability of tendons is limited and in almost all of the cases, the biomechanical properties of a healed tendon are not as good as that of an uninjured tendon [14,29]. Reduced tendon strength leads to thickening and an increased stiffness of the tendon, making it more prone to re-rupture [14,29]. 1.3. Clinical relevance Classification and terminology of different tendon overuse injuries are still not agreed upon completely. It is commonly accepted that while tendinitis is accompanied by the infiltration of inflammatory cells, the actual inflammatory tendinitis is almost non-existent in human tendon. However, acute, swollen, inflammatory reaction can be seen in epitenon as well as the loose connective tissue surrounding the tendon [15]. The pathological changes taking place within tendon itself in overuse injuries is tendinosis. Tendinosis (hypoxic, hyaline and mucoid degeneration, tendolipomatosis etc.) and acute tendon rupture are most likely caused by intratendinous degenerations without inflammation [32,33]. This view is supported by the fact that histopathologies of tendinopathy and acute tendon ruptures are identical; the degenerative pathology is just more severe in acute tendon rupture than in tendinopathy [34,35]. Furthermore, the current paradigm is that the onset of tendinosis is caused by hypoxia, (i.e. lack of oxygen) in the diseased tendon [32,33]. Angiogenesis is induced by the cells experiencing hypoxia and in the cells attempt to survive under hypoxia through secretion of soluble growth factors and cytokines, thus recruiting inflammatory cells [32,33]. Increased numbers of inflammatory cells were seen especially in hypervascular regionsof tendinopathy. Due to neither inflammatory exudates nor accumulation of inflammatory cells in tendon bundles being detected, it was concluded that there is no inflammation in the tendinopathy. For example, Alfredson et al., [36] showed that no inflammatory mediators can be measured in the dialysate from chronic Achilles tendinopathy obtained by inserting a microdialysis catheter into the tendon. Furthermore, it should be considered that the great majority of the cells in tissue remodeling and repair are inflammatory cells (mainly macrophages) but their presence does not necessarily mean inflammation. A recent review by Millar et al., [37] challenges this dominating paradigm by suggesting that the lack of observation of an acute inflammatory infiltrate does not exclude a role for inflammation in the etiology of tendinopathy and that there might be the probability of preceding initial inflammation without clinical symptoms, finally leading to tendinopathy or spontaneous tendon rupture. Tendinopathy is a multifactorial condition and the precise role of inflammation in the tendinopathy process is still debatable and most likely cannot be viewed under the label of “one-size-fits-all”. Therefore, future research has to carefully investigate inflammatory components in the various sub-types of tendinopathies. The term tendinopathy is used throughout this article to describe overuse disorders affecting tendons, i.e. conditions that do not involve tendon rupture, but are accompanied by chronic pain. Healthy tendon has a poor natural healing ability due to hypocellularity and hypovascularity [38] and very low, almost nonexistent metabolic rate [18], but as long as the ruptured parts remain in contact to each other and the epitenon is intact, healing without surgical intervention is possible [21]. Therefore, there is an ongoing debate as to whether to treat ruptured tendons surgically or conservatively, as these treatments provide almost the same outcome in randomized controlled trials in some tendons such as the Achilles tendon [39,40].In Achilles tendon ruptures, surgical intervention reduces the risk of rerupturing but on the other hand increases the risk of other complications such as surgical wound infections [41,42]. With respect to surgical treatment of rotator cuff, tears does not lead to a better functional outcome, but reduces pain and disabilities [43]. Moreover, the outcome also depends on patient's age, degree of tendon degeneration and extent of laceration [44]. Rupture of the patellar tendon leads to abolition of knee extension [45]. To restore the extensor apparatus of the knee, surgical treatment is inevitable [46] Sutures are the most common approach to re-establish tendon alignment, whereas bone anchors are needed when there is an avulsion/rupture of tendon from bone. Numerous techniques have been established, each especially adapted to the specific tendon. In some cases, tendon autografts may be necessary to recreate tendon structure, especially in the cases of tendon retraction or loss. These autografts have to be taken from donor sites, resulting in the risk of donor site morbidity [25]. Recently, use of allografts to bridge defects has increased [47,48]. The use of allografts avoids the problem of donor site morbidity but comes with the concern of immune rejection and disease transmission [49]. Overall, surgical repair of ruptured tendons is often unsuccessful and many become chronic tendinopathies [2]. However, not only age or overuse can cause tendon disorders, also several intrinsic factors, including body weight, vascular perfusion, anatomical variants, systemic disease, nutrition and even blood group may be the causative factors [6,50]. More recently, genetic polymorphisms associated with an increased risk for Achilles tendinopathy have been discovered. In the gene encoding for matrix metalloproteinase MMP 13, three different variants have been shown to be associated with Achilles tendinopathy in a south African Caucasian population [51], while two variants of the COL5A1 gene also increase the risk for this disease [52,53]. Acute tendon ruptures and chronic tendinopathies affect a growing number of people, restricting their quality of life and their capability to work. Additionally, they are the cause for the enormous budget spent each year by the worldwide healthcare system. Hence, it is of great interest to develop new effective therapeutic treatments, like stem cell-based tissue engineering, growth factor cocktails or other drugs, for curing tendon diseases and augmenting tendon repair. 2. Stem cells in tendon Stem cells are cells with the ability to differentiate into a multitude of cell types. Due to their potential to differentiate into tenocytes, a high proliferative and synthetic activity, the secretion of paracrine factors and the ability to exhibit immunomodulatory effects to promote tendon regeneration, the use of stem cells in tissue engineering for tendon repair is of great promise. Stem cells of different origins have been analyzed for their effect on tendon healing in vitro and in vivo (Table 2). 355M. Schneider et al. / Advanced Drug Delivery Reviews 129 (2018) 352–375 Table 2 Effect of different stem cell types in tendon repair. Cell type Origin of cells Study model Outcome References Tendon stem/progenitor cells (TPSC) Rat Rat Rat Rat Rabbit Human Rat, patellar tendon, surgical window defect, 1 mm in width, transplantation of TPSCs in fibrin glue, analysis at 1, 2 and 4 weeks Rat, patellar tendon, surgical window defect, 1 mm in width, TPSC-fibrin construct transplantation (with our without CTGF and ascorbic acid treatment), analysis at 2, 4 and 8 weeks. Rat; patellar tendon; surgical window defect, 1 mm in width, transplantation of mock-TDSCs in fibrin glue, Scx-TPSCs in fibrin glue or scaffold only, analysis at 2, 4 and 8 weeks. Rat, patellar tendon, surgical window defect, 1 mm in width, implantation of TPSC cell sheet, analysis 2, 4 and 8 weeks after surgery. Rabbit, rotator cuff tendon, surgical defect, 10 × 5 mm, implantation of TPSC seeded silk-collagen scaffold, analysis 4, 8 and 12 weeks after injury. Rat, patellar tendon, surgical defect, 2 mm diameter, implantation of TPSCs with or without ETM gel, analysis 8 weeks after surgery. Accelerated healing, increased Col production, increased ultimate stress and Young's modulus at week 4. Accelerated and enhanced tendon repair by treated TPSC up to week 8 and 16 compared to untreated TPSC and controls. Shown by histology, ultrasound imaging and biomechanical testing. Better tendon healing in Scx-TPSC group compared to Mock-TPSC and scaffold only. Shown by histology, viva CT, biomechanical testing, immunohistochemistry. Improved healing, increased cellularity, increased ECM production, no differences in Col expression, higher ultimate stress and Young's modulus. Shown by histology, immunohistochemistry and biomechanical testing. More ingrowth of fibroelastic cells, less infiltration of lymphocytes, denser ECM, more physiological native tendon structure, higher Col I and Col III production, increased biomechanical properties. Shown by histology, immunohistochemistry and biomechanical testing. Improved tendon healing in ETM group, thicker and more organized Col fibrils. Shown by histology. [79] [83] [80] [84] [72] [85] Bone marrow mesenchymal stem cells (BMMSCs) Rat Human Rat, Achilles tendon, surgical window defect, Injection of BMMSCs, Analysis after 1, 2 and 4 weeks Rat, Achilles tendon, Collagenase induced injury; implantation of BMMSCs; analysis 2, 4 and 6 weeks after injury. Rat, Achilles tendon, surgical defect, implantation of BMMSC-loaded mesh, analysis 6 and 14 days after injury. Increased tissue repair, higher ultimate failure load, increased Col production. Shown by histology, biomechanical testing and RT qPCR Accelerated healing, increased Col production and better organization, no differences in biomechanical properties. Shown by histology, immunohistochemistry and biomechanical testing Improved tendon healing, increased ECM production and better organization. Shown by histology and immunohistochemistry Increased load to failure ratio after 2, but not after 4 weeks, no difference in stiffness, no difference in tissue organization and Col synthesis. Shown by Histology, immunohistochemistry and biomechanical testing. [100] [101] 356 M. Schneider et al. / Advanced Drug Delivery Reviews 129 (2018) 352–375 Table 2 (continued) Cell type Origin of cells Study model Outcome References Human Rat Rat Rat Horse Rat, Achilles tendon, 2.4 mm punch injury, injection of BMMSCs, analysis 2 and 4 weeks after injury. Rat, Achilles tendon, complete incision, injection of normoxic or hypoxic MSCs, analysis 2 and 4 weeks after incision. Rat, Achilles tendon, 2.4 mm punch, injection of MSC-eGFP or MSC-bFGF, analysis 12 weeks after surgery. Horse, superficial flexor digitorum longus tendon, spontaneous lesion, injection of MSCs, follow up till 2 years after treatment. Faster closure of gap in Achilles tendon, increased ultimate failure load (hypoxic higher than normoxic), increased numbers of mature tenocytes, reduced fibrosis, increased Col I production. Shown by biomechanical testing, histology and immunohistochemistry. No differences in load to failure and stiffness, no differences in Col content and organization. Shown by biomechanical testing and histology. Better ultrasound images, return to full exposure, reduced risk of re-rupture. Shown by ultrasound and follow up analysis. [102] [105] [103] [104] [107] Adipose-tissue derived mesenchymal stem cells (ADMSCs) Horse Rabbit Rat Rabbit Horse, superficial flexor digitorum longus tendon, spontaneous lesion, injection of ADMSCs, analysis 9 to 24 weeks after injection. Rabbit, Achilles tendon, surgical incision, covered with PRP gel or PRP-ADMSC gel, analysis 4 weeks after surgery. Rat, supraspinatus tendon, surgical detachment, implantation of ASDCs in collagen carrier, analysis after 24 h, 1, 2 and 4 weeks. Rabbit, Achilles tendon, cross section, transplantation of ADMSCs, analysis after 14 and 28 days. Horse, superficial flexor digitorum longus tendon, collagenase induced lesion, injection of MSCs 2 weeks after lesion induction, Ultrasound every second week till 16 weeks after injection, tendon biopsy 16 weeks after injection. Rat, Achilles tendon, collagenase induced lesion, injection of MSCs 1 week after lesion induction, analysis 4 or 12 weeks Sonographic improvement of defect, reduced lameness. Shown by MRT. Increased tensile strength, more longitudinally arranged Col fibers, increased Col I production, increased FGF and VEGF synthesis, decreased TGF-βsynthesis. Shown by biomechanical testing, histology and immunohistochemistry. No differences in biomechanical properties, no differences in Col production. Shown by biomechanical testing and histology. Increased structural organization. Shown by histology. No difference in lesion area, increases linearity of Col fibers, no differences in Col I and III expression and synthesis. Shown by ultrasound, histology, immunohistochemistry and qRT-PCR. Lower levels of degenerative changes, higher density of collagen fibers, decreased Col III/Col I ratio. Shown by histology, immunohistochemistry and RT-PCR. [122] [119] [121] [118] (continued on next page) 357M. Schneider et al. / Advanced Drug Delivery Reviews 129 (2018) 352–375 2.1. Tendon stem/progenitor cells In 2007, Bi et al., first demonstrated the existence of stem cells in tendon tissue. They showed that human and mouse tendons contain a minor cell population which possess clonogenic capability, a distinct mRNA expression profile, multipotent and have a high proliferation capability [54]. The existence of stem/progenitor cells (TSPCs) could be confirmed in various tendons and ligaments from different species [31,54–64]. They exhibit classical criteria of adult mesenchymal stem cells, like typical surface antigens, self-renewal, clonogenicity and three-lineage differentiation (adipogenic, osteogenic and chondrogenic) [31,54–64]. In contrast to MSCs of other origins, they express the tendon-related genes scleraxis (Scx), tenomodulin (Tnmd) [16], cartilage oligomeric matrix protein (Comp) and TN-C [54–59]. Various studies have focused on the isolation, characterization and the finding of specific markers of TSPCs (reviewed in [60,61]). TSPCs are positive for some common stem cell markers, which can also be found on the surface of other mesenchymal stem cells (MSCs). They express Sca-1, CD44, CD90, CD90.1, CD105, CD146, Stro-1, nucleostemin, Oct-4 and SSEA-1 but not CD18, CD31, CD34, CD45, CD106, CD117, CD144 and Table 2 (continued) Cell type Origin of cells Study model Outcome References Horse Rat after injection. [273] [120] Stem cells of other sources human (umbilical vein) Human (periodontal ligament, gingivial tissue) Human (induced pluripotent, neural crest) Human (dental pulp stem cells = DSPCs) Rabbit, Rotator cuff, 5 mm punch, injection of MSCs, analysis 4 weeks after surgery. Mouse, subcutaneous implantation of alginate microspheres loaded with TGF-β3 and PDLSCs, GMSCs or BMMSCs, analysis 8 weeks after implantation. Rat, patellar tendon, surgical window defect 1 × 4 mm, implantation of iPSC-NCSCs in fibrin glue or fibrin glue alone, analysis 4 weeks after surgery. Mouse, subcutaneous implantation of DSPC-PGA scaffolds with our without mechanical loading, analysis 8 and 14 weeks after surgery. Reduced tendon tear size, growth of fibroblastic bundles, increased Col I production. Shown by histology and immunohistochemistry. Neoformation of tendon-like structures in all groups, more organized ECM and Col in PDLSC group. PDLSCs show best capability for form tendon-like tissue. Shown by histology and immunohistochemistry. Better repair with denser connective tissue and increased ECM production in iPSC-NCSC group, higher failure load and Young's modulus. Shown by histology and biomechanical testing. Loaded tissue constructs form thicker neotendinous tissue, faster Col maturation, increased expression of Scx, Tnmd and TNC. Shown by histology and immunohistochemistry. [274] [275] [276] [277] Perivascular cells Rat Rat Rat, patellar tendon, window defect 1 × 4 mm, peritenon sutured or peritenon scratched, analysis 1 and 4 weeks after surgery. Rat, patellar tendon defect, transplantation of CTGF pretreated or untreated CD146+ TSPCs, analysis after 2 weeks Faster tendon healing in peritenon sutured group. Shown by macroscopic observation. Improved tendon healing only in CTGF-TSPC group, reorganized collagen orientation. Shown by histology. [131] [132] 358 M. Schneider et al. / Advanced Drug Delivery Reviews 129 (2018) 352–375 Flk-1 [61]. Since there are no molecular markers that allow discrimination between TSPCs, tenoblasts and tenocytes, it is impossible to isolate pure subsets of cell populations from these differentiation stages (Fig. 2). The exact role of TSPCs in tendon maintenance and healing is not completely understood till now. Hence, there is a great need for in vitro and in vivo studies demonstrating their role and location. Recently it was shown that cells simultaneously expressing tendon and pericyte-associated marker genes are localized in the perivascular space of tendon tissues, suggesting that the perivascular niche might be a source of another type of local stem/progenitor cells [55]. Furthermore, it was proposed that there is a regional distribution of different stem/progenitor cells within tendon, namely in the outer tendon sheet (TSPC type I) and within the tendon proper (TSPC type II) (Fig. 1)[31, 65]. Comparison between these subpopulations revealed that the peritenon-derived cells have increased vascular and pericyte markers, while the tendon proper-derived cells are more proliferative and exhibit higher levels of Scx and Tnmd [65]. The study of Bi et al., shows that TSPCs reside in a niche which consists mostly of ECM. Two ECM molecules, namely fibronectin (Fn) and Bgn seem to play an essential role in the control of TSPC function. Tendons of double-knockout mice for Fn and Bgn showed higher cellularity and decreased fibril thickness. TSPCs of this knockout strain exhibited increased colonogenicity and proliferation, while the expression of Scx and Tnmd were reduced, leading the authors to hypothesize that tendon ECM influences TSPC selfrenewal and differentiation and that alteration in ECM composition could lead to tendon malformation and ossification. Conforming data for this hypothesis was also presented in this study, as TSPCs from the Fn/Bgn knockout mice were more responsive to BMP signaling, which leads to increased differentiation towards the osteogenic lineage. Mesenchymal stem cells (MSCs) from different tissue origins display common stem cell properties, but still might have tissue specificcharacteristics and therefore different functions [66]. Since TSPCs show higher clonogenicity, proliferation and multi-lineage differentiation potential compared with bone marrow-derived MSCs (BMMSCs) in vitro [54,60, 67] and also express higher levels of bone morphogenetic protein (BMP) receptor IA, IB and II [68], TSPCs are most likely a distinct cell type from BMMSCs. Furthermore, when implanted subcutaneously, TSPCs formed tendonand enthesis-like structures, while BMMSC implantation led to the formation of bone and bone marrow-like structures [54]. As mentioned above, the transplantation of tissues or cells faces some challenging problems. Transplantation of allogenic cells may lead to an immune reaction. This problem could be overcome by using autologous cells, but the retrieval of such cells can cause donor site morbidity. Another problem that needs to be resolved is that tendon derived cells may undergo phenotypic drift during in vitro expansion. Over time, cell shape and expression patterns of Col I, Col III and Dcn change in human tenocyte culture, if cells are cultivated in monolayer [69–71]. One possibility to avoid cell phenotype lost is to mimicking the natural niche of tendon-derived cells in vitro. In the tendon, tenocytes lay embedded in a dense three-dimensional (3-D) network of collagens, other ECM components and cells. AAs a result, Schulze-Tanzil et al., [72]suggested to cultivate tenocytes in high-density culture, where they form 3-D pellets. This technique led to stable cell morphology and expression patterns of Scx, Col I and Col II over 14 days, indicating that tenocytes retained their phenotypic identity in 3-D culture [72]. An alternative of the 3-D high density culture is a self-assembly model with tendon-derived cells resulting in 3-D tendon cell sheet structure that can be subjected to static [289] or even dynamic axial load. Further proof for the usability of tendon cell sheets formed by TSPCs was provided by a study showing that the implantation of tendon cell sheets in a rat Achilles tendon defect improved the overall tendon healing and reduced the defect size, and resulted in better organized collagen fibers with elongated spindle shaped cells and higher ultimate load, four weeks after surgery [73]. Fig. 2. Differentiation of a TSPC to a tenocyte.The expression profile of a TSPC changes during differentiation to a tenocyte. Tenogenic differentiation is mostly driven byTGF-β2/3 and BMP 12/13. 359M. Schneider et al. / Advanced Drug Delivery Reviews 129 (2018) 352–375 Other relevant ways to sustain stable cell phenotype is TSPC cultivation on adequate 3-D scaffolds that are similar to native tendon ECM molecular composition, organization, topography and overall biomechanical properties [31,74–76]. TSPC is also a mechanosensitive cell population [77], hence subjecting the cells to mechanical stimulation in vitro could provide a relatively simple option to stabilizetheir characteristics during prolonged cell culture periods. The number of studies using TSPCs in tendon defect models has only slowly increased. One of the first studies by Zhang et al., used human TSPCs with or without engineered tendon matrix (ETM) in a rat patellar tendon window defect. They could show that the implantation, especially in combination with the ETM, led to increased tendon healing with the production of thicker and more organized collagen fibrils. In addition, they also reported that cultivation in ETM stimulates proliferation and preserves stemness of TSPCs in vitro, further highlighting the importance of the ECM niche for TSPCs [78]. Most studies analyzing the effect of TSPC implantation on tendon healing use the rat as a model organism. By transplanting GFP-TSPCs in fibrin glue into a rat patellar tendon window defect, Ni et al., showed that TSPCs significantly enhanced tendon healing and were observable in the tendon for two weeks after transplantation. TSPC transplanted tendons exhibited significantly increased tendon healing with increased collagen production and fiber alignment, improved cell alignment, increased ultimate stress and a higher Young's modulus [79]. In an attempt to further improve the positive effects of TSPCs on tendon healing different scaffolds or pre-treatments of cells were used. For example, transduction with Scx prior to implantation enhanced the expression of tendon-related markers in comparison to Mock-TSPCs. ScxTSPCs in a fibrin construct, Mock-TSPCs in a fibrin construct or the fibrin construct only, were transplanted in a patellar tendon defect. In comparison to the Mock-TSPC and fibrin construct only group, healing was improved in the tendons implanted with Scx-TSPCs. They exhibited improvement in fiber arrangement and decreased vascularity and showed no signs of ossification. Regarding biomechanical properties, only at week four did the Scx-TSPC treated tendons show increased ultimate stress. At week eight, no differences between the three groups were observed and Young's modulus did not differ between groups at four or eight weeks after surgery. The authors try to explain these results with the usage of older cells for transplantation, which might have lower differentiation potential. Furthermore, this study does not address the question of whether if the transplantation of Scx-TSPCs increases the production of tendon specificECMinvivo[80]. Along these lines, recent studies compared native TSPCs derived from tendon or periodontal ligament as well as tenogenically enforced BMMSCs via viral Scx over-expression versus BMMSCs for their potential to repair 3 mm complete defect in a rat Achilles injury model and showed that implantation of tendon cells is beneficial for late tendon repair in terms of matrix composition and reduced ossification [81,82]. In vitro treatment with connective tissue growth factor (CTGF) and ascorbic acid led to increased tenogenic proliferation, therefore the effect of such a pre-treatment on TSPCs tendon healing potential was analyzed in a patellar tendon injury model. The pre-treatment of TSPCs led to accelerated tendon healing, eight weeks post-implantation. At 16 weeks, no differences between tendons implanted with pre-treated TSPCs or untreated TSPCs could be observed. At 8 weeks, larger and better aligned fibrils were formed and biomechanical properties were increased, indicating that the pro-proliferative effect of CTGF and ascorbic acid also occurs in vivo and could be useful in accelerating tendon healing [83]. In another study with TSPCs, CTGF and ascorbic acid focussed on forming a TSPC cell sheet by rolling up, which was then named an engineered scaffold-free tendon tissue (ESFTT) [84].The ESFTT was implanted subcutaneously in nude mice and in a patellar tendon window defect in rats. The subcutaneous implantation of ESFTT led to formation of neotendon 12 weeks after surgery. In the patellar tendon window defect, the implantation of ESFTT improved tendon healing significantly. Implanted tendons had augmented ECM production, better collagen fiber alignment, as well as increased ultimate stress and Young's modulus at two, four and eight weeks after surgery [84]. Shen et al., combined allogeneic TSPCs with a knitted silk-collagen sponge scaffold and implanted it in rabbit rotator cuff tendons after creating a surgical defect. The implants did not cause an immunological reaction but led to increased fibro elastic cell ingrowth and reduced infiltration of lymphocytes, 4 and 8 weeks after surgery. At 12 weeks after implantation, the allogeneic TSPC-treated group exhibited increased collagen deposition and had better structural and biomechanical properties compared to the control group in which silk-collagen scaffolds were implanted without TSPCs. How the implanted scaffolds affected the production and organization of ECM has yet to be clarified [85]. As mentioned TSPCs, being a tendon native cell population, hold great promise for understanding tendon cell biology and for being a cell target for therapeutic implantation in tendinopathy and possibly in tendon rupture. A remarkable development in this direction was achieved by research on human autologous tenocyte implantation, where tendon cells were isolated from healthy tendon needle biopsy. After in vitro expansion, the cells were injected into the central tendinopathy of extensor tendons under ultrasound guidance on a single occasion. A 5 year follow-up with 16 patients showed significantly improved clinical and MRI tendinopathy scores concluding a long-term positive effect of the implanted cells [86]. A similar pilot study focusing on treatment of chronic recalcitrant gluteal tendinopathy concluded that autologous tenocyte implantation is safe, with improved and sustained clinical outcome up to 24 months after surgical intervention [87].Atpresent,this technology is already approved in Australia (Orthocell). Despite the promising results indicating the capability of tendonderived cells to improve and accelerate tendon healing in experimental models and to positively influence tendinopathy in humans, there is still a great need to analyze how exactly the cells mediate their beneficial effects to surrounding tissue and how these effects could be further improved. 2.2. Mesenchymal stem cells Tendon-derived stem cells are not the only cell source that can be used for tissue engineering approaches to improve tendon healing, but also stem cells from other origins have provento bepromising. Amongst the different populations of stem cells, the mesenchymal stem cells (MSCs) have received most interest in musculoskeletal tissue engineering. MSCs are stem cells capable of differentiating into cells of one germ line, mesenchyme, i.e. osteoblasts (bone), chondrocytes (cartilage), tenocytes (tendon), myocytes (skeletal muscle) or adipocytes (fat). In the late 1980s, the existence of MSCs in adult tissues was proposed on the basis that subcutaneously or intramuscularly implanted demineralized bone matrix caused the accumulation of multipotent progenitors that formed cartilage and/or bone in adult animals [88]. Since then, tissue engineering studies have focused on fabricating tissue ex vivo, using MSCs of different origins, (e.g. bone marrow, adipose tissue or periodontal ligament) often in combination with suitable scaffolds. According to the International Society for Cellular. Therapy, cells must fulfill three criteria to be acknowledged as MSCs. First, MSCs must be adherent to plastic when maintained in culture. Second, MSC populations must be positive for several antigens such as CD105, CD73 and CD90 but must lack the expression of hematopoietic antigens like CD45, CD34 and markers for monocytes, macrophages and B cells. Third, the cells must be able to differentiate at least to osteoblasts, adipocytes and chondroblasts under standard in vitro differentiating conditions [89]. 2.2.1. Bone marrow-derived MSC Recent studies have highlighted the ability of BMMSCs to differentiate into various connective tissue types and their usability for tissue 360 M. Schneider et al. / Advanced Drug Delivery Reviews 129 (2018) 352–375 They found that Bupivacaine and Ropivacaine are both cytotoxic for TSPCs and reduce their metabolism, while Morphine had no such effect, suggesting that morphine is the drug of choice in clinical practice [62]. Overall, there are few drugs used for the treatment of tendinopathy or tendon injury, despite use in pain relief. However, little is known about how these drugs affect viability, proliferation and expression profiles of TSPCs. Hence, there is a great need of in vitro studies analyzing if drugs have undesirable effects on TSPC survival, proliferation and tenogenic differentiation to enhance tendon repair. More recently, studies focusing on new cellular boosters that could enhance tenogenic differentiation of stem cells and therefore increase the success of stem cell transplantation after tendon rupture have been published (Table 5). Popov et al., analyzed the effects of age on Ephrin (Eph) A4 and Eph B2 expression and their effect on selfrenewal, migration and actin turnover of young and aged TSPCs. The motivation for this study was that aged TSPCs change their expression of different Eph members, enter senescence earlier and have a selfrenewal deficit as well as dysregulated actin dynamics, cell motility and cell matrix interactions [63]. In aged TSPCs, Eph A4 and Eph B2 were downregulated significantly. They further showed that treatment with Eph A4 and Eph B2 can overcome the migration deficit of aged TSPCs and that Eph A4 increases proliferation of aged TSPCs, almost to the level of young TSPCs [64]. In accordance, another study found that a disturbed Eph A signaling is related to age-associated senescence in human cardiac progenitor cells [223]. These findings indicate that Eph signaling is important for the maintenance of stem cell characteristics from different origins. Regarding tendon rupture, implantation of TSPCs overexpressing Eph is potentially a promising approach. One problem with working with TSPCs is that they undergo spontaneous differentiation in vitro. Hence the culture steps necessary between isolation and re-implantation, might lead to the loss of TSPC stemness. One possible way to circumvent this problem might be the administration of retinoic acid receptor (RAR) agonists. A study using high throughput screening identified RAR agonists as strong inducer of Scx expression in TSPCs. Further analysis by the authors found that treatment with a RAR agonist does not influence cell viability or morphology, but that it leads to an upregulation of Scx expression and blocks differentiation into osteocytes, adipocytes or tenocytes. In addition, the treatment also preserved the expression of stem cell markers in vitro [224]. Implantation of TSPCs that have not undergone differentiation during in vitro cultivation, might help to unleash their complete regeneration potential. In terms of stem cells of other origins from tendon regeneration, Mohawk (Mkx) might be a promising candidate for inducing tenogenic differentiation. Overexpression of Mkx in MSCs impaired adipogenic and osteogenic differentiation of MSCs and TSPCs. Furthermore, MSCs overexpressing Mkx formed cell sheets with a larger collagen fibril diameter in vitro and implantation of these cells in a rat Achilles tendon injury model, increased the amount of mature collagen and enhanced the biomechanical capacities of the repaired tendon in comparison to tendons treated with mock-MSCs [225]. Activation of the Rho/Rock signaling pathway could be another way of efficiently inducing tenogenic differentiation in MSCs, since inhibition of this pathway leads to a loss of the elongated phenotype of tenocytes, a reduction in the expression of Scx and Col I and stretch induced morphological changes seen in tenogenic differentiation are impeded [226, 227]. Despite the fact that the Rho/Rock signaling pathway has been suggested to be involved in the differentiation of MSCs [228,229] there are no studies investigating the effect of activators of this signaling pathway on the tenogenic differentiation potential of MSCs. Overall, we have to deepen our knowledge of molecules and signaling pathways involved in tenogenic differentiation (Fig. 2)tobeableto identify adequate boosters of this process, which can then enhance the healing potential of MSCs applied in tendon injuries. 6. Effects of drugs on vasculature and endothelium in tendon healing In the healthy tendon, blood vessels enter the tendon from the myotendinous junction, the bone insertion site and from the paratenon. In sheathed tendon, blood vessels only enter the tendon at a few distinct points, while in tendons containing a paratenon, vessels pass through the tissue more frequently. Since tendons are extended by mechanical load during movement, the vasculature must be compliant to being stretched. Hence, the vessels form curves within the tendon tissue [230]. Due to their limited metabolism and their mechanical function, tendons contain only very little vasculature. In the adult tendon, the relative avascularity is simply caused by the fact that the metabolic rate of tendon is almost non-existent [18,231]. Table 4 Effects of drugs on tendon stem/progenitor cells. Drug Effect on TSPCs Source Dexamethasone Increased synthesis of dickkopf1, inhibition of the classical WNT/β-catenin pathway, differentiation of TSPCs to adipocytes [220] Inhibition of differentiation to tenocytes, downregulation of Scx expression [219] Low concentrations increase, high concentrations reduce cell proliferation, upregulation of non-tenogenic differentiation, formation of fatty tissues, cartilage-like tissues, and bony tissues [218] Dose-dependent inhibition of proliferation, collagen production, colony formation and expansion [216] Trimacinolone Reduced proliferation, increased adipogenic differentiation [221] Bupivacaine Reduced cell viability and metabolism, induction of apoptosis [62] Ropivacaine Reduced cell viability and metabolism, induction of apoptosis at higher concentrations [62] Morphine No cytotoxic effect, no effect on cell metabolism, survival or apoptosis [62] Sclerosin agents Sclerosin injections result in sclerosis, shrinkage of neovessels in various tendinopathies and have positive effect on the tendon tissue [280–285] Bevacizumab Alone or in combination with platelet rich plasma accelerates and improves tendon healing in rodent models [286,287] Digoxin Impedes calcification and promotes tenogenesis of TSPCs in vitro through inhibition of HIF-2alpha [288] Table 5 Novel boosters of tenogenesis. Component Effect on stem cell Source Ephrin A4, Ephrin B2 Eph A4 increases proliferation of aged TSPCs, Eph A4 and Eph B2 increase cell motility, rescue migration deficit of aged TSPCs and improve their actin turnover. [64] Mohawk Overexpression of Mkx impairs adipogenic and osteogenic differentiation of MSCs, increases Scx expression and leads to the formation of cell sheets with larger Col fibril diameters. Implantation of Mkx-TSPCs in rat Achilles tendon injury model leads to increased amounts of mature Col and better biomechanical capacities. [225] Retinoic acid receptor agonists RAR agonists induce Scx expression in TSPCs and block differentiation to adipocytes, osteocytes or tenocytes, while maintaining expression of stem cell markers. [224] Rho/Rock agonists Inhibition of Rho/Rock signaling leads to loss of Scx and Tnmd expression and the tenocyte-like phenotype of MSC under tenogenic conditions. Inhibition of Rho/Rock signaling impedes stretch induced morphological changes of MSCs and upregulation of tenogenic gene expression [226] [227] 367M. Schneider et al. / Advanced Drug Delivery Reviews 129 (2018) 352–375 Persistent hypoxia is the major driver of tendinopathy [30]. The histological outcome of tendinopathy, (i.e. tendinosis), is the outcome of persistent hypoxia in the tendon tissue [30,35]. Hypoxic changes are even more severe in tendon rupture than tendinopathy and the hypoxic changes are the major predisposing factor for acute tendon ruptures [34,232]. To survive under hypoxia, the cells secrete angiogenic growth factors (e.g. VEGF) in the hope of inducing angiogenesis to the area requiring oxygen [200,233,234]. Thus, neoangiogenesis is a typical symptom of chronic tendinopathies and tendon rupture, accompanied by an increase in VEGF expression [235–237]. The role of neovessels for degenerative tendon disorders is poorly understood (reviewed in [231]). One theory associates the area of newly grown microvessels with pain in tendinopathy, since nerve structures are often in close relation [199, 238]. This view is supported by the fact that VEGF also stimulates nerve (axon) growth and could be the reason why nerves generally follow blood vessels in the human body [239].Thusinchronic tendinopathies, hypervascularity is a sign of attempted repair and might be a contributory factor to pain while in an acute injury, the increased vascularity seems to be essential for tendon repair [26].When considering the role of neovessels in tendinopathy, it is fundamental to understand that the neovessels are non-functional blood vessels, which do not have proper perfusion and do not deliver oxygen and nutrients to the cells needing them, resulting in hypoxia persisting in the tissue surrounding them [233,234] So, the chronic persistence of neovessels seen in tendinopathy should be always considered a sign of failed repair. Endothelial function is regulated by a finely balanced equilibrium between vasorelaxing and vasoconstricting mediators. In these processes nitric oxide (NO) seems to have an important role. NO is produced by two enzymes, NO synthase 1 (NOS1) and NOS2. NOS1 is a constitutively expressed enzyme that produces tiny amounts of NO to keep blood vessels open (“dilated”). In turn, NOS2 is an inducible enzyme expressed in inflammation and produces large quantities of NO. NO derived from NOS2 reacts with toxic superoxides and stimulates the production of peroxynitrites and free radicals, eventually predisposing to endothelial dysfunction [240,241]. In normal, un-injured tendon there is little to no NOS present but after injury, expression of NOS 1, 2 and 3 was upregulated in a rat rotator cuff and Achilles tendon injury model with a peak, 7 days post injury [242,243] and feeding rats with a NOS inhibitor, significantly reduced tendon healing [244]. VEGF induces the expression of NOS2 and the increased NO concentrations encountered in the ruptured tendon after the injury are related to active angiogenesis and the VEGF-driven vasodilation as well as the inflammation cascade. In human rotator cuff samples, excised during surgical repair, NOS activity was found in 7 out of 10 samples [245]. Overuse of tendon also results in an over-expression of NOS isoforms and this might contribute to degenerative changes mediated by increased levels of metalloproteinases or cytotoxicity [246,247]. To what extent and how NOs influence endothelium in tendons and how this contributes to tendon injury are questions not yet completely understood. There have been attempts to treat tendinopathies with NO (reviewed in [244]). In three randomized clinical trials, NO was administered to the area of tenderness via a glyceril trinitrate (GNT) patch in three different conditions: tennis elbow, Achilles tendinosis and supraspinatus tendinosis. In all three conditions, the NO GNT patch led to enhanced clinical recovery that is demonstrated in reduced pain, increased range of motion and increased strength compared to a placebo GNT patch. In summary, one needs to understand that there is neither tissue repair nor regeneration without oxygen. In turn, oxygen needs to be delivered to tissue undergoing repair by blood vessels. Thus, the blood vessels are crucial for any tissue repair after injury. The increased vascularity seen in the persistent neovessels in tendinopathy is a sign of failed repair. It is well established in cancer research that the neovessels are non-functional; they do not have proper perfusion and do not deliver oxygen and nutrients to the tissue The hypoxia persists in the tissue surrounding them [233,234]. Thus, the focus on tendinopathies should be on stabilizing the non-functional neovessels to provide adequate oxygen and nutrients supply to the tendon. Neovascularization is essential for the early stages of tendon healing. Hence it might be interesting to study the effect of drugs that influence vascularization at different time points after tendon injury and pursue strategies that stabilize the vasculature to a functional one [248,249]. Angiogenic inhibitors have been most extensively studied in the context of cancer, since cutting tumor blood supply is a promising approach. Many of them have passed or are close to passing FDA approval and are already used for therapy of cancer or age-related muscular degeneration [250]. However, anti-angiogenic drugs have been a major disappointment in the treatment of cancer as the survival benefit derived from them, has been rather minimal [233,234,248]. The mechanism of resistance to the currently available antiangiogenic therapies in tumors as well as in retinopathy are actually related to the eradication of the neovessels, which worsens the underlying ischemia and drives the formation of new neovessels by alternative molecular mechanisms [233,234,248]. Thus, the proposed molecular mechanism for future antiangiogenic therapies is one in which the angiogenic blood vessels are “normalized”to stable ones to alleviate the hypoxia [233,234,248, 249] The “normalized”blood vessels are functional, they have the proper perfusion inside them and can carry enough oxygen and nutrients for tissue regeneration to take place [233,234,248]. As described above, first animal studies using anti-VEGF treatment to accelerate tendon healing have reported promising results, hence the creation of a finely balanced VEGF levels seems to be desirable. However, it is wellestablished in other injury models, such as wound and fracture healing that tissue regeneration cannot be obtained if the injury is treated with VEGF-inhibitors [251,252]. Pro-anigiogenic substances are of great interest in the early stages of tendon healing and especially when it comes to transplantation of scaffolds, since in this instance, the formation of a robust new vascular network is essential for their incorporation to the healing tissue. Ideally, scaffolds could be directly loaded with short half-life angiogenic agents, such as growth factors and they should have desired release kinetics from the scaffolds. 7. Conclusion Our understanding of the exact mechanisms of tendon healing and the precise roles that different cell types play in this process is still limited and requires forthcoming research focusing at solving concrete issues that have been formulated thanks to the research efforts of the past decades. At present, the result of treatments for ruptured tendon is often poor, but stem/progenitor cells hold a great promise for outcome improvement, although we need to further investigate how they can be forced or stabilized into the tenogenic lineage and to what extent they can be beneficial for early and late tendon healing stages. Stem/ progenitor cells of the tendon tissues have been identified and studied in vitro and in vivo; however, we are still lacking tools to segregate with high level of purity the immature cells from terminally differentiated cells. Special attention should be given in the tendon research to identify surface markers for cell sorting and to standardize protocols for enriching and sustaining different tendon-derived cell populations. In the possible mode of using stem/progenitor cells to augment tendon healing decorating them with growth factors or supporting them by cellular boosters might be a good way to increase their healing potential. A very promising approach with regards to their homing to the site of injury is to equip them with vascular homing peptides that can guide them to neoangiogenic activity centers. Regarding the potential of stem/progenitor cells as a therapeutic agent, it is also very important to clarify their survival and integration rates as well as to follow their fate and function over longer periods of time in vivo. When stem/progenitor cells are implemented into various experimental animal models for tendinopathy or tendon injury, we have to carefully and critically 368 M. Schneider et al. / Advanced Drug Delivery Reviews 129 (2018) 352–375 consider their reflection to the human conditions and tendon size dimensions. Future efforts to optimize or develop clinically relevant animal models have to be undoubtedly pursued in order to achieve preclinical models with valid translation to human and veterinary medicine. Another important future perspective for understand what influences the and influencing tendon healing process and tendinopathy is to decipher the current ambivalent roles of inflammation and inflammatory cells, and in the following steps to design and apply strategies to steer them in order to experimentally examine whether certain inflammatory pathways can result in beneficial or detrimental outcomes of tendon healing or can lead to amplification or resolution of tendinopathy. It is possible that in the next decade that specificinflammatory cell types with positive influence on tendon repair will be identified and hence, the field can move towards regenerative immunological strategies to treat certain forms of tendon diseases. There is already some clinical evidence where autologous implantation of tendon-derived cells for human tendinopathy shows positive effects in term of safety and clinical scores. It would be very interesting to investigate the exact engagement of the transplanted cells that are processed to repair and their cross-talk to endogenous cells, as well as if such strategy is foreseeable for treatment of tendon ruptures. Taken together, Achilles would have been happy to know of the progress achieved so far but like any true hero, would seek further perfection by trying to find answers to the many open questions and exploratory possibilities in the field in order to shape up efficient rescue strategies for ruptured or diseased tendons. This review hopes to encourage scientists to engage in studies aiding in better comprehension of the potential of stem/progenitor cells to improve and speed up the healing of injured tendons. Acknowledgements D. D. acknowledges the support for tendon research received over the years from the German Research Foundation (Grants: DFG DFG DO1414/1-1, DO1414/3-1 and PO1718/1-1) and T. 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