The pathogenesis of tendinopathy: balancing the response to loadingS. Peter Magnusson, Henning Langberg and Michael Kjaer Abstract Tendons are designed to withstand considerable loads. Mechanical loading of tendon tissue results in upregulation of collagen expression and increased synthesis of collagen protein, the extent of which is probably regulated by the strain experienced by the resident fibroblasts (tenocytes). This increase in collagen formation peaks around 24 h after exercise and remains elevated for about 3 days. The degradation of collagen proteins also rises after exercise, but seems to peak earlier than the synthesis. Despite the ability of tendons to adapt to loading, repetitive use often results in injuries, such as tendinopathy, which is characterized by pain during activity, localized tenderness upon palpation, swelling and impaired performance. Tendon histological changes include reduced numbers and rounding of fibroblasts, increased content of proteoglycans, glycosaminoglycans and water, hypervascularization and disorganized collagen fibrils. At the molecular level, the levels of messenger RNA for type I and III collagens, proteoglycans, angiogenic factors, stress and regenerative proteins and proteolytic enzymes are increased. Tendon microrupture and material fatigue have been suggested as possible injury mechanisms, thus implying that one or more ‘weak links' are present in the structure. Understanding how tendon tissue adapts to mechanical loading will help to unravel the pathogenesis of tendinopathy.
Magnusson, S. P. et al. Nat. Rev. Rheumatol. 6, 262–268 (2010); published online 23 March Tendon tissue has an essential role in transmitting exerted on a tendon will depend on its cross-sectional contractile forces to bone to generate movement, and area. Human tendons, including the commonly afflicted is therefore uniquely designed to withstand consider- patellar and Achilles tendons, typically have a fracture able loads (up to 8 times body weight) during human stress of 100 MPa. However, most tendons are only sub- locomotion.1–3 However, repetitive loading often results jected to stresses of up to 30 MPa,15 which gives tendons in overuse injuries, such as tendinopathy, which is a a reasonable safety margin, although the Achilles tendon common clinical condition characterized by pain during might experience stresses of up to 70 MPa.1,16 Tendon activity, localized tenderness upon palpation, swelling of microrupture, which is presumably associated with a lack the tendon and impaired performance.4,5 Tendinopathy is of load in a local area along with its associated fibroblasts, a problem in both elite and recreational athletes, as well as has been suggested as a possible injury mechanism for in the workplace.6–8 In some elite athletes, the prevalence tendinopathy.6,17 It has also been suggested that fatigue, can be as high as 45%,6,9–11 and the symptoms, as well defined as the time-dependent damage that occurs in as any reduction in performance, might be long lasting response to cyclic loading, might be an injury mechanism (many years, in some cases).12 The injury mechanism is in tendon.18 The precise mechanism of injury that leads to currently poorly understood. Human tendons have tradi- tendinopathy remains unknown, but the proposed mecha- tional y been considered largely inert structures, but are nisms imply that there are one or more ‘weak links' in the now known to be metabolical y active in their response to tendon structure that result in the pathological response mechanical loading.13,14 Understanding how tendon tissue of the fibroblast.
adapts to mechanical loading is key to understanding the Institute of Sports patho genesis of tendino pathy, and will thus provide Structure of tendon tissue Medicine, Bispebjerg Hospital and Center for the basis for preventing these overuse injuries. In this The organization of tendon follows a strict hierarchi- Healthy Aging, Faculty Review, we discuss current knowledge of how the various cal pattern (Figure 1).19 Collagen molecules are orga- of Health Sciences, Bispebjerg Hospital, components of the human tendon respond to acute and nized precisely to give rise to the characteristic 67 nm Building 8, University of chronic loading.
D-periodization that forms fibrils. The collagen mol- ecule is 300 nm in length and 1.5 nm in diameter,20 Bispebjerg Bakke 23, 2400 Copenhagen NV, Force and the tendon
and aggregated molecules of the fibril are stabilized by The average tensile stress (which relates to the force covalent intermolecular crosslinks.21,22 The crosslinks (S. P. Magnusson, H. Langberg, M. Kjaer).
transmitted and the area over which it is transmitted) bind the col a gen molecules to one another and thereby confer integrity on the fibril. Groups of fibrils then form Correspondence to: Competing interests fibers known as fascicle bundles, which final y co mprise The authors declare no competing interests.
the tendon proper. There are at least 28 different col agen 262 MAY 2010 voluMe 6
0 Macmil an Publishers Limited. Al rights reserved proteins, but tendon is predominantly made up of type I Key points
col agen.23 The fibril ar col agen is embedded in a hydro- philic extra cel ular matrix consisting of proteo glycans, ■ Tendons are metabolically active and respond readily to both loading glycoproteins and glyco saminoglycans, which are involved in the develop ment, organization and growth ■ Mechanical loading results both in protein synthesis and degradation of collagen control of tendon.24 ■ without sufficient rest (24 h) after exercise, net loss of collagen might occur that leaves the tendon vulnerable to injury Force transmission within the tendon ■ Tendinopathy is associated with neovascularization, but newly formed blood The tendon might be functional y regarded as a single vessels (and nerves) disappear during healing force-transmitting structure, but it remains unknown ■ The pathogenesis of tendinopathy can be accelerated by overloading if force is transmitted evenly throughout the tendon, and therefore whether the stress–strain on tendons is homo- geneous. whether there is a ‘weak link' in the force trans- Tendon, 0.5–1.0 cm2 mission and how it might adapt to loading conditions remain enigmatic issues.
Fascicles from the anterior and posterior portion of the human patellar tendon display substantially dif- ferent mechanical properties.25 lateral force trans- mission between adjacent fascicles is relatively smal , and therefore the fascicles might be considered to be func- tional y independent structures.26 The fact that sliding Fascicle, Ø 0.1–4 mm can occur between fascicles might be advantageous as, for example, tendons wrap around bones. The inter- fascicular space contains fibroblasts, capil aries, nerves and small- diameter fibrils, 26 and it remains unknown if the structures in this space would be adversely affected by disproportionately large shear or possible focal adhe- sions, or both. It is, however, important to underline that Fibril, Ø 30–300 nm mechanical stimulation of fibroblasts located between fascicles is important for the synthesis of collagen and the release of growth factors.
The col agen fibril is considered the fundamental force- transmitting unit of the tendon,27 although the actual length of fibrils in mature tendon remains an unresolved issue, which precludes a detailed understanding of tendon Molecule, Ø 1.5 nm force transmission. In fact, suggestions that fibrils are continuous28,29 and discontinuous exist,30–33 with currently Figure 1 The different hierarchical levels (tendon–molecule) of the human Achil es
no unequivocal proof of either proposal. Discontinuous tendon. a The whole human tendon comprises col agen fascicles. Inset: stereo
fibrils would require force to be transferred between adja- micrograph of two adjacent human col agen fascicles with intact interfascicular loose cent fibrils, and functionally continuous fibrils would connective tissue. The crimping pattern of the fascicle is visible. b MRI of the human
mean that the fibrils assume most of the tensile load. Thus, Achilles tendon, which can withstand stresses up to 100 MPa (scale in cm). c The
it remains unknown whether individual fibrils might fascicle consists of col agen fibrils, fibroblasts, proteoglycans, glycoproteins and sustain microruptures, or whether other components of glycosaminoglycans. d TeM of parallel aligned fibrils, which are the fundamental
the extracel ular matrix are damaged owing to large shear tensile-bearing units of tendon. Lower right corner inset: TeM cross-sectional area showing the fibril diameter distribution (30–300 nm). The interfibril ar space is the forces between fibrils.
hydrophilic extracellular matrix, consisting of proteoglycans, glycoproteins and The tropocollagen molecule comprises three poly- glycosaminoglycans that are involved in the development, organization and growth peptides arranged as a triple-helical structure stabilized control of tendon. e The col agen fibril has a quarter-stagger arrangement of col agen
by hydrogen bonds.34 The col agen molecules are orga- molecules. Crosslinking of the col agen molecules to one another confers integrity nized in a precise pattern and an important contributor on the fibril. f Atomic force microscopy image of an isolated single human fibril
to the mechanical properties of the tendon is the inter- showing the characteristic (67 nm) D-band periodicity that represents the alignment molecular crosslinks.21,22 During loading, the triple helix of collagen molecules. g The col agen molecule is made up of three polypeptide
of the tropo collagen molecule might elongate, the gap α-chains to form a triple helix. Abbreviation: TeM, transmission electron micrograph.
between the longitudinal y arranged molecules of the fibril might increase, or a relative slippage might occur between fibroblasts and their cell nuclei, located between fibrils and laterally adjacent molecules.32,35–37 Individual colla gen in the interfascicular space, undergo deformation, which molecules have a fracture modulus that far exceeds that might be important in the mechanical signal transduction of the tendon fibril,34,38 and are therefore unlikely to be pathway of this tissue.39,40 loading can potential y place the ‘weak link'. However, it is unknown to what extent the strain on several components of the tendon that might proposed gliding mechanisms at the level of the molecule contribute to an ‘injury' or material fatigue that requires will affect the associated crosslinks. During tensile loading, repair. such a repair process might comprise a fine balance nATURe RevIews rHeuMAToLogy volUMe 6 MAY 2010 263
0 Macmil an Publishers Limited. Al rights reserved in normal tissue,50,52 whereas the mRnA expression levels of some proteoglycans (for example, decorin and versican) remain relatively unchanged.51 MMPs are important for the normal turnover of tendon proteins during homeo stasis and repair, but these enzymes and their inhibitors might Protein synthesis also be involved in the pathology of tendon injuries.53 Net synthesis h after Degradation exercise Treatment of some types of cancer using MMP inhibitors results in a tendinopathy-like condition that disappears on cessation of treatment.54,55 In insertional regions (regions at which the tendon interfaces with the bone) and areas of tendons that are subjected to compression, mRnA for cartilage-like molecules such as col agen II, aggrecan and Protein degradation sox9 are upregulated.56 Figure 2 Schematic representation of col agen synthesis and degradation. Acute
Changes in protein levels exercise in humans is followed by an increase in both the synthesis and degradation The protein levels of type I col agen decrease whereas those of collagen. Over the first 24–36 h, this response results in a net loss of collagen, but is followed by a net synthesis 36–72 h after exercise. Repeated training with rest of type III col agen increase in tendinopathy tissue.57,58 periods that are too short can result in a net degradation of the matrix and lead to Although the expression and protein content of col agen overuse injury.65,66,111 type III are thereby correlated, the up regulation of col a- gen type I expression does not result in any net increase in between synthesis and degradation of the various compo- col agen I content. The mechanism behind this apparent nents of the extracel ular matrix. However, it should also discrepancy is unknown, but it supports the view that in be noted that too little stimulation (relative inactivity) tendinopathic tendons the normal homeostasis of col a- might also offset such an anabolic–catabolic balance.41 gen I is disturbed. The amount of enzymatic crosslinking of col agen increases, whereas the level of nonenzymatic Pathology of tendinopathy
crosslinking is unchanged or reduced in tendinopathy.59,60 Histological changes Final y, the levels of tenascin C protein increase.61 Typical pathological changes that occur in tendino- pathy include reduced numbers and rounding of fibro- Mechanobiology of fibroblasts
blasts, an increase in the content of proteoglycans, Fibroblasts (tenocytes) are the predominant cel type in glyco saminoglycans and water, hyper vascularization tendon and are responsible for the production of col a- (with nerve ingrowth) and dis organized col agen fibrils. gen and other matrix proteins. Fibroblasts also release and Immuno histochemical analysis of the affected tissue shows respond to growth factors that regulate protein synthesis. the presence of substance-P- positive nerve fibers and It has been shown that tendon fibroblasts surrounded by adrenergic receptors in injured but not healthy tissue.42 biglycan and fibromodulin within the tendon not only Inflammatory cel s have not been detected in tendino- respond to growth factors and can synthesize col agen, pathy tissue.43 There are, however, a greater number but that these ‘niched' fibroblasts exibit stem-cell-like of apoptotic cel s in tendinopathy tissue,44 which most properties,62 and that matrix proteins, such as biglycan likely arises through the activation of c-Jun n-terminal and fibromodulin, are important for the expression of kinase and caspase-3 pathways occurring secon dary to scleraxis, a transcription factor that is involved in tendon mechanic al loading.45–47 differentiation and col agen synthesis.63 Molecular changes Strain and collagen synthesis Changes in mRNA levels Mechanical loading of tendon results in an acute increase Interestingly, the molecular ‘blueprint' of tendinopathy in col agen expression and increased col agen protein syn- is quite different from that of tendon rupture, implying thesis in animals and humans.64,65 This elevated col agen that the pathogenesis of tendinopathy and tendon rupture expression is probably regulated by the strain imparted differs.48–50 elevated levels of messenger RnA (mRnA) on the fibroblast, which can induce a 2–3-fold increase can be demonstrated for type I and III col agens, proteo- in col agen formation that peaks around 24 h after exer- glycans (for example, biglycan and fibromodulin),51 angio- cise and remains elevated for up to 70–80 h (Figure 2).65,66 genic factors (for example, vascular endothelial growth The degradation of collagen proteins also increases in factor [veGF]), aggre can, proteins that are required for a response to exercise,66 probably early on and to a greater stress and regeneration response (for example, heat shock extent than col agen synthesis (Figure 2). The levels of protein [HsP]), fibronectin and tenascin C, and proteolytic markers for proteolysis, such as MMPs or col a gen degra- enzymes (for example, a disintegrin and metalloproteinase dation fragments, are elevated in response to exercise,66,67 [ADAM]-12, ADAMTs2, ADAMTs3 and some matrix and this process represents part of the physio logical metallo proteinases [MMP1, MMP2, MMP9, MMP13 and response to loading. After cessation of exercise and up MMP23]).50 By contrast, levels of mRnA encoding MMP3, to 18–36 h thereafter (improved training status short- MMP10 and MMP12 and tissue inhibitor of metallo- ens this time frame) there is a negative net balance in proteinase (TIMP)-3 are lower in tendinopathy tissue than col ag en levels, whereas the balance is positive (anabolic 264 MAY 2010 voluMe 6
0 Macmil an Publishers Limited. Al rights reserved in relation to collagen) for up to 72 h after exercise (Figure 2). These data indicate that a net increase in col a- gen requires a certain restitution period, and that with- out sufficient rest a continuous loss of col agen is likely to occur, which might render the tendon vulnerable to injury. Tendinopathy arises perhaps, therefore, as a result of an imbalance between the synthesis and breakdown of matrix proteins, especial y col agen.41 Interestingly, the relationship between tendon loading and col agen syn- thesis increases up to a certain point, then levels off with increasing workload (Figure 3), which indicates Tendon collagen synthesis (% per h) 0.00 Rest that fibroblasts are unable to further synthesize col agen Loading repetitions beyond this upper limit. The fact that pro col agen expres- Figure 3 Response of collagen to loading. The synthesis of
sion is upregulated in the same manner in the tendon col agen, based on the number of loading repetitions from independent of muscle contraction mode (eccentric, iso- human studies, to a 36 km running,111 b 1 h of maximal
metric or concentric)64 supports the notion that fibroblast knee kicking65 or c 10 times 10 repetitions
strain regulates the col agen protein synthesis response. of knee extension (70% 1 repetition maximum). The graph It is hypothesized that insufficient recovery time will tilt indicates a similar increase in collagen synthesis the balance between col agen synthesis and degradation, independent of exercise volume (repetitions), which resulting in a net catabolic state.
suggests that there is a ceiling effect in collagen synthesis. It also indicates that adding exercise repetitions (cumulative load) wil not increase col agen synthesis further, but potential y increase degradation and further amplify a Habitual loading (as occurs in response to training) wil negative net balance in collagen.
result in a higher rate of collagen synthesis in the basal state simply as a result of the constant effect of loading in microdialysis fluid representing the tendon inter stitial from the previous 24–48 h; this effect can be seen at the concentration.80 A key regulator of col agen syn thesis is level of the whole tendon as tendon hypertrophy.68 The rate IGF-1, which has a stimulatory effect on col agen protein of degradation also increases with training to ensure that synthesis in vitro and in vivo.79,81 TGF-β and CTGF the overall turnover is high, but not to the same extent stimulate fibroblasts within the patella tendon to syn- as the increase in synthesis, which allows for a small—but thesize collagen,82 and exercise seems to enhance this consistent—positive net balance of col agen.69 Habitual effect.83 Interestingly, the expression of both IGF-1 and training thus results in a higher turnover of collagen, TGF-β mRnA rises in response to exercise independent whereas inactivity lowers col agen synthesis and turn- of muscular contraction type,78 which suggests that both over.70 This result il ustrates why activity even in the pres- growth factors are important regulators of col agen syn- ence of tendino pathy might be better for the regeneration thesis in tendon. surprisingly, inactivity by suspension of of the tendon tissue than complete inactivity.
the hindlimb in rats or by lower limb casting in humans The fact that col agen and matrix proteins are impor- also resulted in an initial increase in the levels of IGF-1 tant in the development of tendinopathy is supported mRnA,84 which indicates an unloading IGF-1 response,85 by the fact that polymorphisms in the genes that encode or a compensatory increase in the synthesis of growth col ag en and tenascin C are associated with a higher than factors to counteract the inactivity-induced drop in col a- normal risk of developing tendinopathy (Box 1).71,72 In gen synthesis. when activity is resumed after a period addition to col agen, other matrix proteins also respond of rest, the expression of col agen is again normalized.84 to loading. several proteoglycans, such as decorin, ver- These findings demonstrate that inactivity does not sican, aggrecan, lumican, fibromodulin, keratocan and follow a pattern opposite to that of the loading response, proteoglycan 4, increase their turnover in response to and that this pattern might reflect a protective mechanism loading to maintain homeostasis in the tendon,73–77 which towards the loss of tendon tissue during inactivity. In any further supports the use of loading activity in the treat- case, these responses do not favor inactivity as a treatment ment of tendinopathy. Final y, the expression of enzymes for tendinopathy.
involved in protein crosslinking is also upregulated with exercise, which lends additional support to the notion Cytokines, prostaglandins and inflammation that tendons respond readily to loading.64 A potent response to exercise is a rise in the levels of Il-6 in the peritendinous tissue;80 this rise seems to parallel Molecular response to exercise
that of col agen synthesis. Infusion of Il-6 in the vi cinity of the tendon tissue has been found to induce col a gen exercise results in an increase in the mRnA levels and protein synthesis similar to that evoked during exercise in the tissue concentrations of growth factors such as (M. B. Andersen, J. Pingel, M. Kjaer, H. langberg, unpub- insulin-like growth factor 1 (IGF-1), transforming growth lished work). This result supports the view that cytokines factor β (TGF-β), connective tissue growth factor (CTGF) are potent stimulators of col agen synthesis in tendon. and interleukin (Il)-6. This response has been shown in estro gen might have an inhibitory role in the adapta- animal tendons,78 in human tendon homo genate,79 and tion response of col agen and matrix tendon to loading.86 nATURe RevIews rHeuMAToLogy volUMe 6 MAY 2010 265
0 Macmil an Publishers Limited. Al rights reserved Tendinopathy itself is often, but not always,98 associ- Box 1 The genetic component of tendinopathy
ated with neovascularization and elevated intratendinous Genetic variations have been implicated in the development of tendinopathies. The blood flow99–101 that seems to normalize during the course collagen, type V, alpha 1 (COL5A1) and TNC genes encode the col agen alpha-1(V) of exercise-based conservative treatment.100 Increased flow chain and tenascin C, both of which are important structural components in tendons during exercise probably represents a physio logically and ligaments; variations within these genes, along with variations in the gene important response, whereas an elevated flow in the encoding matrix metalloproteinase 3, have been shown to cosegregate with chronic Achilles tendinopathy.71,72 The collagen alpha-1(V) chain is involved in the assembly resting state accompanies tendinopathy. However, rather of collagen fibers and influences fiber diameter, and variations in this component than being important in the pathogenesis of tendino pathy, might alter collagen strength. Similarly, tenascin C is known to be involved in the latter response represents a secondary regenerative the response of collagen to mechanical loading in a dose-dependent manner. The phenomenon. Indeed, the elevated flow during loading genes encoding these proteins have also been shown to be associated with anterior might be advantageous for tendinopathy. In patients with cruciate ligament ruptures.109,110 These data indicate that genetic variations might clinical signs of tendinopathy and hypervascularization, be involved in the development of certain tendon pathologies.
it has been suggested that the primary source of pain is the result of nerves growing intimately with the new Young women—especial y if taking estrogen-containing vessels into the tendons.102 It has been demonstrated that oral contraceptives—demonstrate lower basal levels of tendon tissue injury (partial rupture model) leads to both collagen and a lower increase in collagen synthesis in an angiogenic response103 and marked nerve ingrowth, response to loading compared with males.87–89 This result as well as the presence of substance P and calcitonin- might explain why women show an attenuated adaptive gene-related peptide, both of which are involved in pain tendon response with habitual loading,90 and why they transmission.104,105 These newly formed nerves and blood might need longer for tendon adaptation to loading. The vessels disappear during healing, a process that is accel- lower increase in col agen synthesis in response to loading erated with physical activity and delayed with prolonged might also explain why women are more susceptible to inactivity in the recovery phase.106,107 How nerve ingrowth certain soft tissue overload injuries.91 The mechanism occurs in tendinopathy is unclear, but the process seems to remains unknown, but as estrogen levels are inversely occur subsequently to alterations in protein synthesis, and related to the levels of IGF-1 in tissues, estrogen might might therefore explain why clinical pain occurs when the exert its inhibiting effect indirectly via attenuating the tendinopathy is already quite advanced.
response to IGF-1.
A rise in the concentration of prostaglandins in tendon Conclusions and perspectives
tissue is part of the physiological response to load ing, Understanding how tendon tissue adapts to mechanical and blocking this response has been shown to inhibit the loading, and how and when this process is attenuated synthesis of collagen protein (s. G. Petersen, l. Holm, during tendinopathy, will contribute to our understand- M. Kjaer, unpublished work). such inhibition is in line ing of the pathogenesis of this condition. In part, the with what is known to occur in skeletal muscle contractile limited knowledge of the pathogenesis of tendinopathy protein92 and for skeletal muscle stem cel s (satellite cel s).93 resides in the fact that the actual injury mechanisms are levels of inflammatory mediators in tendino pathy are not quite advanced before symptoms are experienced by elevated in the resting state,94 which further supports the the patient. new methods, such as tissue biopsy sam- notion that tendinopathy is not an inflammatory condi- pling, infusion of growth factors and determining local tion. However, the inflam matory response might increase tissue reactions to acute loading or overloading by use of immediately after exercise, despite the absence of inflam- microdialysis, have yielded promising new information matory cel s in the chronical y overloaded tendons, indi- on the turnover of the connective tissue. An intervention cating a susceptibility of the overloaded tissue towards an model that combines immobilization with acute loading increase in inflammation with loading. This result would might also unveil the pathways of overloading in fragile explain the difference between the lack of inflammatory (immobilized) tissue. To study the actual injury mecha- observations during surgery and the documented positive nism and the early stages of the injury, it might be useful short-term effect of anti- inflammatory medication (for to turn to animal models, the use of which has already example, glucocortico id injection) in tendinopathy.
been demonstrated.108 The definitive establishment of knowledge about the injury mechanism is an important Vascular and neural regulation
step in the development of more effective treatment and Poor blood supply has been implicated as a factor con- tributing to tendon injuries, but tendon vascularization appears ample both around and inside the tendon in patients with tendinopathy.95,96 During exercise, the blood flow of tendon can increase by up to seven-fold, and it is we searched for original articles focusing on tendinopathy mainly regulated by the release of prosta glandins. This in MeDLINe and PubMed, published between 1970 and response only represents 20% of the maximal capacity of 2009. The search terms we used were "tendinosis", the tendon during ischemic reperfusion,97 and therefore "tendinitis", "tendinopathy", "collagen" and "fibroblast". blood flow is remarkably low during rest. In individuals All papers identified were english-language, full text who undergo extensive physical training, resting blood papers. we also searched the reference lists of identified flow is not elevated.
articles for further papers.
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© Copyright 2003 by the American Chemical Society Volume 42, Number 44 NoVember 11, 2003 Current Topics Structure and Function of Malic Enzymes, A New Class of Oxidative Gu-Gang Chang*,‡ and Liang Tong§ Faculty of Life Sciences, Institute of Biochemistry, Proteome Research Center, National Yang-Ming UniVersity, Taipei 112, Taiwan, and Department of Biological Sciences, Columbia UniVersity, New York, New York 10027


Open Your "I's": Inquire, Inspire, and Innovate By Charles Rashall In today's ultra-competitive business environment, companies have trimmed every ounce of fat and now must find ways to improve the top-line. To that end, innovation provides one of the most important tools to generate new revenue producing opportunities. Innovation requires the proper work environment and set of practices that promote inquiry, discovery, insight, and inspiration. Surprisingly, some of the greatest innovations