`
`of neointimal cells PCNA-positive) with declining proliferation at 14 days
`(9.6 ± 1.3% PCNA-positive) and 28 days (1.1 ± 1.0% PCNA~positive).
`In human stented arteries, cellular proliferation has been evaluated in
`atherectomy specimens from patients with in-stent restenosis. In a study
`of I 0 peripheral arterial lesions (6 femoral arteries, 3 iliac arteries, and 1
`subclavian artery) with stents implanted 4 to 25 months, lesions from the
`stented
`segments were hypercellular with
`actin positive
`cells
`demonstrating high proliferative activity (24.6 ± 2.3% PCNA-positive).
`In contrast, another study of restenotic tissue obtained by coronary
`atherectomy from stents in place 2.5-23 months showed a relatively
`hypocellular extracellular matrix; cellular proliferation (determined by Ki-
`67 staining) was rare [10]. The reasons for the conflicting results among
`these atherectomy studies are uncertain and are probably due to variability
`and small size of the samples obtained by percutaneous atherectomy.
`
`Stent Endothelia/ization
`In a variety of
`experimental animals (rabbit, dog, pig), complete
`endothelialization of the stent surface may be seen as early as 7 days to
`approximately 4 weeks [28, 45, 56, 69]. Data from humans regarding
`stent endothelialization is limited. Anderson et al reported coronary stent
`endothelialization in a single stent 21 days post-implant [2]. Van
`Beusekom et al demonstrated complete endothelial stent coverage by 3
`months in saphenous vein bypass grafts [67]. Repair on the luminal
`surface via reendothelialization may be a critical process in vascular
`healing via prevention or limitation of luminal thrombosis. Further,
`inhibition of continued neointimal growth has been felt to be a result of a
`restored endothelial surface. However, recent data demonstrate that the
`presence of an endothelial surface in and of itself is insufficient to inhibit
`the neoi~tima~ normal endothelial function and/or non-endothelium(cid:173)
`dependent factors may be relatively more important than the presence or
`absence of an endothelial surface in suppressing neointimal expansion
`[68].
`
`Neointimal Growth
`a
`The mature neointima consists of smooth muscle cells
`111
`proteoglycanlcollagen matrix. Experimental
`studies
`demonstrate
`organization of the intimal thrombus by 7-14 days with smooth muscle
`cell migration from the media and adventitia [ 61]. Cell proliferation
`within the maturing neointima is accompanied by matrix synthesis and the
`fonnation of a thick cellular neointima by 8 weeks [7, 56, 65]. In human
`atherosclerotic arteries, neointimal development is delayed compared with
`experimental animals, but is clearly present in aiJ stents implanted 230
`days (Figure 3) [2, 22, 30, 32]. Proteoglycans are macromolecules that
`
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`A Pathologist's View ofStenting 147
`
`FIGURE 3
`
`In-stent neointimal (n) growth 16 weeks after placement of a PaJmaz(cid:173)
`Schatz stent in the right coronary artery (panel A). Underlying
`fibrous plaque (p) is present. A higher power view of the neointima
`(panel B) demonstrates the proteoglycan-rich neointima (n) containing
`numerous smooth muscle cells. Near stent struts (*), an organizing
`thrombus (arrowhead) is seen. Fibrous plaque (p) and necrotic core
`(ric) are indicated. (Movat pcntachrome stain)
`
`are an important component of the extracellular matrix . They consist of
`specific glycosaminoglycans
`(chondroitin sulfate, dermatan sulfate,
`heparan sulfate, keratin sulfate) linked to a protein core via 0-gylcosidic
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`148 A Farb eta/
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`linkages which are themselves bound to hyaluronic acid. Versican and
`hyaluronic acid have been identified in the neointima after stenting in
`human arteries [ l 0]. Recently, we demonst rated that simi Ia r strong
`inununohistochemical staining for hyaluronic acid and chondroitin sulfate
`in the neointima of stented coronary arteries compared with PTCA-treated
`coronary arteries matched for the duration following stent deployment or
`PTCA (Figure 4 ). Neointimal smooth muscle cell density was also similar
`in matched stented and PTCA-treated coronary arteries [22].
`The
`neointimal area was greater in the stented segments compared with PTCA
`
`arteries (3.06 ± 1.63 mm 2 versus 1.94 ± 1.20 mm 2, respectively, p<0.05).
`
`However IEL area was larger (11.61 ± 2.14 mm2) with stent placement
`compared with PTCA (7. 88 ± 2.13 mm2
`, p==O.OOOl) so that the neointima
`corrected for artery size (neointima/IEL) was similar in stents and PTCA.
`
`Ultimate histologic success is dependent on lumen 'area and neointima
`growth within the stent [22]. In contrast to PTCA alone, slenling prevents
`negative remodeling of the artery as a component of the restenosis
`
`FIGURE 4 (Caption on page 149)
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`A Pathologist's View ofStenting
`
`149
`
`FIGURE 4 Caption (for Figure on page 148)
`
`Neointimal cellularity and proteoglycans in chronic coronary stents
`compared with balloon angioplasty (PTCA).
`A1: Low power micrograph of left circumflex coronary artery
`containing a Gianturco-Roubin stent placed 10 months antemortem.
`The neointima is outlined by arrowheads, and the stent strut is
`identified (*). The neointima is relatively thicker over the stent strut
`compared with the remainder of the arterial segment. Scale bar 0.20
`mm.
`A2: Alpha actin staining of neointima (n) identifying smooth muscle
`cells. Scale bar 0.12 mm.
`A3: Strong alcian blue stain of the neointima (n) showing presence of
`proteoglycans, predominately of chondroitin sulfate and hyaluronic
`acid. Scale bar 0.12 mm.
`Bl: Low power micrograph of left anterior descending coronary
`artery treated with PTCA 13 months antemortem. The neointima is
`outlined by arrowheads, and the residual lumen (L) is indicated.
`Scale bar 0.16 mm.
`B2: Alpha actin staining of neointima (n) identifying smooth muscle
`cells. The cell density is similar to the stented artery (A2). Scale bar
`0.20 mm.
`B3: Alcian blue stain of the neointima (n) showing strong staining for
`proteoglycans, similar in intensity to the stented artery (A3). Similar
`to stents, chondroitin sulfate and hyaluronic acid are the major
`constituents of the neointimal proteoglycans after PTCA. Scale bar
`0.08 mm.
`(Movat pentachrome: A1 and B1; smooth muscle actin immunostain:
`A2 and B2; alcian blue A3 and B3J. Modified with permission from
`reference 22.
`
`In our analysis of stented human coronary arteries, the mean
`process.
`neointimal area and neointima area/stent area in successes were 2.2 ± 1.1
`mm2 and 0.39 ± 0.12, respectively, versus 3.9 ± 1.9 mm2 and 0.68 ± 0.15
`in failures, respectively (p<0.006 and p<O.OOOl).
`There were no
`differences between successes and failures with respect to areas of the
`EEL, IEL, plaque, or stent [22]. There was a significant linear correlation
`(p<O.OOOl, R2=0.54) between increased neointimal growth and increased
`stent size relative to the proximal reference coronary artery lumen [22].
`Therefore, stent over-sizing relative to the reference lumen appears to be
`an undesirable goal in deployment.
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`150 AFarbetal
`
`Responses to Arterial Injury and Neointimal Growth
`Placement of intra-arterial stents is always associated with vascular injury
`ranging from superficial damage to the endothelium and superficial layers
`of the media to full thickness medial rupture and adventitial stretch.
`Schwatz et al.
`showed the important positive correlation between the
`severity of arterial
`injury in stented porcine coronary arteries and
`subsequent neointimal growth {59]. Other experimental studies suggest
`injury, and
`important
`relationships among
`inflammation, vascular
`neointimal growth.
`In stented nonathcrosclerotic balloon-injured rabbit
`iliac arteries, peak monocyte adherence was observed 3 days after stcnting
`\Vith maximal proliferation seen at 7 days {52]. There was a linear
`correlation (R2=0.82-0.92) between monocyte adherence and neointima at
`14 days [52]. Further, increased vascular injury correlated with increased
`neointimal growth, inflammation and thrombus formation [ 5 11.
`
`the underlying vessel
`characteristics of
`the
`effect of
`The
`(morphologically nonnal media versus absent media due to medial tear)
`adjacent to the stent strut was addressed in a porcine double arterial injury
`In areas where the arterial media was absent (damaged by
`model [8].
`balloon a11gioplasty 4 weeks prior to stcnt placement), neointimal
`thickness was greater than at strut sites that were adjacent to an intact
`internal elastic lamina and media [8] . In stented atherosclerotic human
`coronary arteries, increased arterial injury was associated with increased
`stent-associated inflammation {22].
`Furthermore, in human coronary
`arteries containing stents for > 30 days, neointimal thickness at stent strut
`sites was greater when medial damage (medial laceration or rupture) was
`present (0.69 ± 0.29 mm) compared with stntts in contact with plaque
`(0.33 ± 0.26 mm, p<O.OOO 1) or stmts in contact with an intact media
`(0.29 ± 0.23 mm, p<O.OOOI) [22]. Taken together, the data from
`experimental work
`showing
`correlations
`among
`arterial
`InJUry,
`inflammation and neointima, and observations from human stents
`demonstrating increased inflammation and neointimal growth when medial
`damage is present suggest that a reduction of arterial injury during
`catheter-based interventions with stents may have a b~neftcial cff~ct on
`late neointimal growth. Novel devices that do not require very high
`balloon inflations to accomplish close apposition of the stcnt to the arterial
`wall (eg, self-expanding bare stents) are currently in clinical trial [25].
`
`STENT GRAFTS
`
`Offering the potential advantages of endovascular stents and bypass
`grafts, and deliverable via a percutaneous approach, stcnt grafts have
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`A Pathologist's View of Stenting
`
`151
`
`been under active investigation for the treatment of cardiovascular
`disease. Previously, interpositional autologous or synthetic grafts have
`been the standard surgical approach fo~ the management of peripheral
`arterial athero-occlusive and aneurysmal disease [ 1, 3, 54, 70]. However,
`long-term patency of synthetic grafts <6.0 mm in diameter have been
`complicated by thrombosis and intimal hyperplasia at the anastomotic
`sites [57]. The higher rate of graft thrombosis using synthetic material as
`compared with autologous veins may be secondary to
`incomplete
`endothelialization of the graft [57] as endothelialization > 1.5 em from the
`anastomosis of a synthetic interpositional grafts is rare. Additionally,
`smooth muscle cell proliferation and migration
`lead
`to neointimal
`hyperplasia secondary to medial injury to the host vessel during the
`creation of the anastomosis itself [60].
`
`Building on the work on stents by Dotter, Cragg, Balko, and Paroldi
`pioneered the development of stent grafts for treatment of vascular disease
`and aneurysms
`[4, 15, 47].
`Currently,
`intraluminally deployed
`endovascular stent grafts (tubular designs with or without bifurcated
`segments) are becoming an alternative for the management of iliofemoral
`occlusive disease [37-39, 48]. These grafts do not require the creation of
`a sutured anastomosis and thus do not cause anastomosis-associated
`vascular injury [72].
`
`ln patients and in experimental preparations, autologous vems or
`synthetic materials
`such
`as
`polyester
`(Dacron) or
`expanded
`polytetrafluoroethylene (ePTFE) have been used as graft material for
`covered stents [16, 46, 49]. Because it is dilatable, PTFE can be
`fashioned as a small profile stent graft system, delivered to the arterial
`treatment site via a percutaneous sheath, and balloon-dilated to the
`appropriate size [15]. However, because of a 30% elastic recoil, PTFE
`grafts must be over-dilated [ 15]. In contrast, Dacron is inelastic and is
`not dilatable in situ [ 15]. Therefore, precise sizing of Dacron stent grafts
`before deployment is necessary for optimal clinical outcome.
`
`In "unsupported" stent grafts, the stents are located at the ends of the
`graft material and act as tethering points of the stent graft to the arterial
`wall. "Fully-supported" stent grafts, in which the stent is present for the
`entire length of the graft, provide greater longitudinal support and radial
`strength and are less prone to kinking [15]. The stent itself may be on the
`inside, the outside, or completely enveloped within the graft material.
`Stent placement inside of the graft allows for enhanced sealing of the
`interface of the graft material with the surrounding vessels [ 15].
`However, this endoskeleton design provides for an uneven flow surface
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`152 A Farb eta/
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`and greater turbulence as stent struts protrude into the lumen. Protruding
`stent struts cause focal areas of low shear, which increase the likelihood of
`local thrombus deposition. Complete interweaving of the stent within the
`graft (ie, graft material on both sides of the stent) may be advantageous
`for long-tem1 outcome as poor patency rates have been associated with
`endoprostheses in which the graft is unsupported and/or loosely attached
`to the stent [ 18, 73]. Further, completely enveloping the stent within the
`body of the ePTFE graft provides a more uniform luminal surface
`compared with a graft placed outside of the stent.
`
`An advantage of covered stent grafts is prevention of embolization of
`friable atherosclerotic plaque material during device deployment. The
`ability for bare stents to penetrate the plaque necrotic core and potentially
`liberate atheroembolic material (Figure 5) was evident in our study of
`human coronary stent implants; the lipid core was focally penetrated by
`stent struts in 26% of arterial sections [22]. Plaque prolapse between
`stent struts, especially extrusion of the thrombogenic lipid core, are
`important events that may be effectively prevented via the placement of a
`stent graft.
`
`Endothelia/ization
`In interposition grafts, healing and endothelialization proceed from the
`anastomotic ends towards the center of the graft [ 12]. Endothelialization
`appears to be superior
`in endoluminally placed PTFE stent grafts
`compared to interpositional grafts [ 41].
`The importance of graft
`proximity to endothelial cells was shown in a study by Bull et al in which
`interpositional ePTFE grafts implanted in canine carotid arteries showed
`endothelial cell migration from the native artery extending only 1.0 em
`beyond the ends of the device [6].
`In contrast, wrapping the external
`surface of the graft with a vein resulted in complete endothelialization of
`the ePTFE graft. Endoluminal deployment of a porous stent graft places
`the device in close proximity to a source of endothelial cells (vessel wall
`lining and vasa vasorum of the surrounding artery) along the entire length
`of the device and may be associated with exposure of the graft to
`physiologically
`important
`local concentrations of growth
`factors,
`cytokines, or other intercellular messengers, such as nitric oxide, which
`can diffuse through the porous graft [ 60]. These diffusable factors may
`further augment endothelialization in contrast to interposition grafts in
`which endothelialization proceeds from the ends of the graft only. The
`optimal pore size for graft endothelialization and healing is 60-90 f.liD
`[26].
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`A Pathologist's View of Stenting
`
`153
`
`FIGURE 5 (Caption on page 154)
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`154 A Farb et al
`
`FIGURE 5 Caption (for Figure on page 153)
`
`A 77 year old woman presented with an acute myocardial infarction
`and was treated with direct balloon angioplasty and stenting of the
`right coronary artery. Refractory myocardial no-reflow developed
`In the stented
`resulting in cardiogenic shock and cardiac arrest.
`portion of the right coronary artery, there was focal penetration by
`multiple stent struts into a large hemorrhagic necrotic core (nc, panel
`A). Several penetrating and non-penetrating stent struts ar·e indicated
`(*). At higher power (panel B), a penetrating strut (*) is better
`visualized within the necrotic core (nc) that is rich in cholesterol clefts.
`The end (arrowhead) of the ruptured fibrous cap (fc) is present.
`Numerous small intramyocardial coronary arteries were occluded by
`atheroemboli containing cholesterol clefts (cc's, panel C) that were
`responsible for the myocar·dial no-reflow. A potential advantage of
`slent grafts over bare
`stents
`is
`a
`reduced
`frequency of
`atheroembolism. (Movat pentachrome: A and B; hematoxylin-eosin:
`C)
`
`1 njlammatioll
`Dacron stent graft placement in experimental animals produces acute
`inflammation and a giant cell reaction associated with the graft and
`extending into the adjacent vessel wall [34]. Clinically, this inflanm1atory
`response has been postulated to correspond to the perivascular thickening
`observed by magnetic resonance imaging that lasts 4-6 weeks [35] and a
`"post-implantation" syndrome characterized by fever, leukocytosis, and
`elevation in serum C-reactive protein (5, 17].
`In human endovascular
`stent graft explants, a foreign body type reaction was seen when the
`device had an external wrap on the PTFE or if placed within the adventitia
`[3 8] .
`
`Neoi11timal formatiml, entlothellalization, and final healing
`In
`interposition grafts., neointimal thickening occurs at the surgical
`anastomosis as .a result of smooth muscle cell migration and. proliferation
`secondary to medial injury in the host artery [ll, 13, 23, 40]. Reduced
`neointimal growth is potential advantage of endoluminally placed grafts;
`Ombrellaro et al.
`found
`that
`intimal hyperplasia was greater
`in
`conventionally placed grafts as compared to endovascular grafts [42].
`However, it must be recognized that neointimal growth along the length of
`a intraluminally placed stent graft will be proportional to the arterial
`injury associated with deployment. The use of self-expanding stent grafts,
`rather than balloon-expandable stents, may result in less arterial injury
`[9] . Marin described histopathologic findings from 7 stent grafts
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`A Pathologist's View ofStenting 155
`
`explanted from humans from 2 weeks to 7 months post-deployment [38].
`Organized thrombus within the graft was present at 3 weeks [38]. An
`endothelium was present in the perianastomotic region at 6 weeks and
`extended 1-3 em from the ends of the graft at 3 months [3 8]. There was
`little neointimal development within the graft [38]. A subsequent
`angiographic study demonstrated less neointimal growth in the PTFE(cid:173)
`covered portion of a Palmaz stent graft versus the uncovered portion of
`the device, suggesting that the presence of PTFE may inhibit smooth
`muscle cell migration into and proliferation within the graft neointima
`[37].
`
`HEMOBAHN STENT GRAFT
`
`We recently completed an evaluatjon of the long-term patency and healing
`characteristics of the HEMOBAHN™ stent graft in normal canine iliac
`and femoral arteries [71] . This device consists of a nitinol stent lined with
`an ultrathin ePTFE material. The thickness of the ePTFE used in this
`device (I 00-~m) is approximately five times thinner than the standard
`commercial1y available ePTFE used in surgically placed vascular grafts.
`The internodal distance (between two solid nodes of PTFE) is 3 0 ~m, and
`a nonporous FEP/ePTFE laminate (I .0 mm width) bonds the graft to the
`stent along its entire length with 1.0 mm gaps so that half of the graft
`surface area remains porous. Further, unlike other endoprostheses in
`which the graft is sutured only to the ends of the stent [ 18], the ePTFE in
`this device is completely interweaved with the stent providing longitudinal
`support.
`
`In this study, these stent grafts were placed with fluoroscopic and
`intravascular ultrasound guidance in canine iliofemoral arteries, and stent
`grafts were analyzed at two weeks, one month, three months, six months,
`and twelve months post-deployment. All stent graft implants were
`successfully deployed in the desired locations without foreshortening. All
`devices were widely patent at all time points . Two weeks after
`implantation, there was fibrin deposition covering 70-80% of the luminal
`surface and an inflammatory infiltrate near the graft material and the
`surrounding nitinol wires (Figure 6). At one month, there was increased
`fibrin deposition between the endoprostheses and the native artery, the
`inflammatory infiltrate was minimal, and no giant cell reaction was
`evident. Neointimal thickness in the mid-region of the device was less at 1
`month (0.42 ± 0.02 mm) than at 2 weeks (0.65 ± 0.07 mm), most likely
`secondary to organization of mural thrombus. Three months after
`deployment, there was nearly complete healing of the space between the
`
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`A Pathologist's View o[Stenfing 157
`
`ultrasound). There was minimal neointimal hyperplasia at the interface of
`the endoprosthesis and native arterial wall. Arterial injury, a determinant
`of late neointimal growth, was mild with this device; there was focal
`medial compression but no medial laceration or rupture. The self(cid:173)
`expanding property of the nitinol stent used, in contrast to balloon(cid:173)
`expanded stent grafts, may be an important feature in limiting damage to
`the underlying artery. Overall, the pattern of pathological responses-(cid:173)
`early mural
`thrombus associated with
`inflammation
`followed by
`neointimal growth--is similar to that observed in bare stenting in human
`atherosclerotic arteries.
`
`FIGURE 7
`
`Hemobahn stent graft placed in canine iliofemoral arteries and
`evaluated 6 months post-deployment. The neointima (n) is fully
`organized consisting mostly of SMCs in a proteoglycan and collagen(cid:173)
`rich matrix. A thin layer of neointima is also present between the
`outer layer of the graft and the media (m). (Hematoxylin-eosin stain)
`
`Endothelialization was assessed by scanning electron microscopy. At 3
`months, 75% of the surface of the graft was covered by endothelial cells,
`and at 6 and 12 months, there was 90-99% coverage (Figure 8).
`Endothelial cells were predominately spindle shaped and oriented in the
`direction of flow. There were no adherent platelets or inflanunatory cells
`on the endothelial surface, suggestive of a functional endothelial lining. In
`previous studies, approximately two and a half times thicker ePTFE lined
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`A Pathologist's View ofStenting
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`159
`
`stent grafts were associated with incomplete endothelialization in the
`canine
`abdominal
`aortic
`aneurysm mode
`[ 44].
`There was
`endothelialization only at the end stent grafts using approximately five
`times thicker ePTFE [42].
`
`this device may have augmented
`in
`The ultrathin ePTFE used
`endothelialization via enhanced
`trans-graft cell migration.
`In an
`experiment designed to support the occurrence of trans-graft cell
`migration, four HEMOBAHN devices were wrapped with a nonporous
`material, poly (tetrafluoroethylene-co-hexafluoropropylene) [FEP], and
`implanted in canine iliofemoral arteries.
`FEP prevents endothelial
`migration to the luminal surface. In stent-grafts completely enveloped by
`FEP, only the proximal and distal ends of the device were endothelialized
`while non-occlusive mural thrombi were noted in the non-endothelialized
`mid-region of the endoprosthesis. In contrast, there was nearly complete
`endothelialization of devices wrapped with FEP only at the proximal and
`distal ends.
`
`CONCLUSION
`
`Vascular morphology after steriting in human atherosclerotic arteries
`demonstrates the fol1owing sequence: thrombus formation and acute
`inflammation earJy after deployment with subsequent neointimal growth.
`Increased inflammation early after stenting is associated with medial
`injury, and medial damage and oversizing relative to the proximal
`reference lumen correlate with increased neointimal thickening. Stent
`grafts are novel devices designed to treat athero-occlusive and aneurysmal
`diseases via a percutaneous approach. A reduced incidence of plaque
`embolization is likely with the use of a covered stent compared to a bare
`stent via avoidance of uncovered stent strut penetration into the necrotic
`core of atherosclerotic plaques. One may expect to encounter similar
`vascular responses to endoluminal stent grafts (thrombus, inflammation,
`and neointimal growth) as seen with bare stenting, and it is unknown
`whether the presence of graft material will provide a further stimulus for
`inflammation
`in an atherosclerotic substrate.
`The self-expanding
`HEMOBAHN
`stent
`graft,
`associated with
`nearly
`complete
`endothelialization, excellent luminal patency, and minimal neointimal
`growth, is a promising device for further study.
`
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`
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`160 A Farb eta/
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`6. Bull, DA, GC Hunter, H Holubec, et al. Cellular Origin and Rate of
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`11. Clowes, A W, MM Clowes, 1 Fingerle, MA Reidy. Regulation of
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