Publications by authors named "Sandra L Johnson"

17 Publications

  • Page 1 of 1

Pediatric tri-tube valved conduits made from fibroblast-produced extracellular matrix evaluated over 52 weeks in growing lambs.

Sci Transl Med 2021 Mar;13(585)

Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA.

There is a need for replacement heart valves that can grow with children. We fabricated tubes of fibroblast-derived collagenous matrix that have been shown to regenerate and grow as a pulmonary artery replacement in lambs and implemented a design for a valved conduit consisting of three tubes sewn together. Seven lambs were implanted with tri-tube valved conduits in sequential cohorts and compared to bioprosthetic conduits. Valves implanted into the pulmonary artery of two lambs of the first cohort of four animals functioned with mild regurgitation and systolic pressure drops <10 mmHg up to 52 weeks after implantation, during which the valve diameter increased from 19 mm to a physiologically normal ~25 mm. In a second cohort, the valve design was modified to include an additional tube, creating a sleeve around the tri-tube valve to counteract faster root growth relative to the leaflets. Two valves exhibited trivial-to-mild regurgitation at 52 weeks with similar diameter increases to ~25 mm and systolic pressure drops of <5 mmHg, whereas the third valve showed similar findings until moderate regurgitation was observed at 52 weeks, correlating to hyperincrease in the valve diameter. In all explanted valves, the leaflets contained interstitial cells and an endothelium progressing from the base of the leaflets and remained thin and pliable with sparse, punctate microcalcifications. The tri-tube valves demonstrated reduced calcification and improved hemodynamic function compared to clinically used pediatric bioprosthetic valves tested in the same model. This tri-tube valved conduit has potential for long-term valve growth in children.
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http://dx.doi.org/10.1126/scitranslmed.abb7225DOI Listing
March 2021

Biologically-engineered mechanical model of a calcified artery.

Acta Biomater 2020 07 16;110:164-174. Epub 2020 Apr 16.

Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, United States; Department of Chemical Engineering & Materials Science, University of Minnesota, Minneapolis, MN, United States. Electronic address:

Vascular calcification is a commonly occurring pathological process and is recognized as an independent prognostic marker for cardiovascular morbidity and mortality. Recent progress in developing novel therapies to modify vascular calcification is critically hampered due to the lack of reliable in vitro experimental models that recapitulate the structural and mechanical attributes of calcified arteries. In this study, we show the ability to model the behavior of diffuse vascular calcification in vitro using biologically-engineered grafts approximating the composition, structure, and mechanical properties of arteries. Transmural calcification was achieved by exposing the acellular grafts of collagenous ECM to complete medium containing elevated Calcium (Ca) and Phosphate (P) concentrations. It was found that increasing the serum concentration from 2% to 10% increased the extent and degree of calcification based on histochemical, ultrastructural, chemical and thermal analyses. The presence of variably-sized spherical calcific deposits within the matrix further confirmed its morphological similarity to pathologic calcification. Mechanical testing demonstrated up to a 16-fold decrease in compliance due to the calcification, consistent with prior reports for calcified arteries. The model developed thus has potential to improve the design and development of interventional devices and therapies for the diagnosis and treatment of arterial calcification. STATEMENT OF SIGNIFICANCE: The presence of extensive vascular calcification makes angiographic/interventional procedures difficult due to reduced arterial compliance. Current attempts to develop safe and effective non-surgical adjunctive techniques to treat calcified arteries are largely limited by the lack of a physiologically relevant testing platform that mimics the structural and mechanical features of vascular calcification. Herein, we developed an off-the-shelf calcified artery model, with the goal to accelerate the pre-clinical development of novel therapies for the management of arterial calcification. To the extent of our knowledge, this is the first report of an in vitro tissue-engineered model of diffuse arterial calcification.
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http://dx.doi.org/10.1016/j.actbio.2020.04.018DOI Listing
July 2020

AI, Machine Learning, and Ethics in Health Care.

J Leg Med 2019 Oct-Dec;39(4):427-441

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http://dx.doi.org/10.1080/01947648.2019.1690604DOI Listing
June 2020

A completely biological "off-the-shelf" arteriovenous graft that recellularizes in baboons.

Sci Transl Med 2017 Nov;9(414)

Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA.

Prosthetic arteriovenous grafts (AVGs) conventionally used for hemodialysis are associated with inferior primary patency rates and increased risk of infection compared with autogenous vein grafts. We tissue-engineered an AVG grown from neonatal human dermal fibroblasts entrapped in bovine fibrin gel that is then decellularized. This graft is both "off-the-shelf" (nonliving) and completely biological. Grafts that are 6 mm in diameter and about 15 cm in length were evaluated in a baboon model of hemodialysis access in an axillary-cephalic or axillary-brachial upper arm AVG construction procedure. Daily antiplatelet therapy was given. Grafts underwent both ultrasound assessment and cannulation at 1, 2, 3, and 6 months and were then explanted for analysis. Excluding grafts with cephalic vein outflow that rapidly clotted during development of the model, 3- and 6-month primary patency rates were 83% (5 of 6) and 60% (3 of 5), respectively. At explant, patent grafts were found to be extensively recellularized (including smoothelin-positive smooth muscle cells with a developing endothelium on the luminal surface). We observed no calcifications, loss of burst strength, or outflow stenosis, which are common failure modes of other graft materials. There was no overt immune response. We thus demonstrate the efficacy of an off-the-shelf AVG that is both acellular and completely biological.
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http://dx.doi.org/10.1126/scitranslmed.aan4209DOI Listing
November 2017

Implantation of completely biological engineered grafts following decellularization into the sheep femoral artery.

Tissue Eng Part A 2014 Jun 25;20(11-12):1726-34. Epub 2014 Feb 25.

1 Department of Biomedical Engineering, University of Minnesota , Minneapolis, Minnesota.

The performance of completely biological, decellularized engineered allografts in a sheep model was evaluated to establish clinical potential of these unique arterial allografts. The 4-mm-diameter, 2-3-cm-long grafts were fabricated from fibrin gel remodeled into an aligned tissue tube in vitro by ovine dermal fibroblasts. Decellularization and subsequent storage had little effect on graft properties, with burst pressure exceeding 4000 mmHg and the same compliance as the ovine femoral artery. Grafts were implanted interpositionally in the femoral artery of six sheep (n=9), with contralateral sham controls (n=3). At 8 weeks (n=5) and 24 weeks (n=4), all grafts were patent and showed no evidence of dilatation or mineralization. Mid-graft lumen diameter was unchanged. Extensive recellularization occurred, with most cells expressing αSMA. Endothelialization was complete by 24 weeks with elastin deposition evident. These completely biological grafts possessed circumferential alignment/mechanical anisotropy characteristic of native arteries and were cultured only 5 weeks prior to decellularization and storage as "off-the-shelf" grafts.
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http://dx.doi.org/10.1089/ten.TEA.2013.0550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4029045PMC
June 2014

Paediatric expert witness.

J Paediatr Child Health 2013 Aug 29;49(8):611-3. Epub 2013 Mar 29.

Discipline Paediatrics and Child Health, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.

Paediatricians may be asked to provide expert opinion in paediatric cases that come under legal consideration. This article provides suggestions to assist paediatricians in this role and emphasises their duty to the court when giving expert opinion.
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http://dx.doi.org/10.1111/jpc.12168DOI Listing
August 2013

Scanning electron microscopy evaluation of endothelialized tissue-engineered constructs.

Authors:
Sandra L Johnson

Methods Mol Biol 2013 ;1001:325-40

Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA.

Scanning electron microscopy (SEM) is an important technique for evaluation of the efficiency of endothelialization of tissue-engineered constructs incorporating a surface endothelial cell layer. Here, we describe methodologies for the preparation of such constructs for SEM analysis that are applicable to a broad range of tissue-engineered constructs.
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http://dx.doi.org/10.1007/978-1-62703-363-3_27DOI Listing
September 2013

Hypoxic culture and insulin yield improvements to fibrin-based engineered tissue.

Tissue Eng Part A 2012 Apr 5;18(7-8):785-95. Epub 2011 Dec 5.

Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.

We examined the effect of insulin supplementation and hypoxic culture (2% vs. 20% oxygen tension) on collagen deposition and mechanical properties of fibrin-based tubular tissue constructs seeded with neonatal human dermal fibroblasts. The results presented here demonstrate that constructs cultured under hypoxic conditions with insulin supplementation increased in collagen density by approximately five-fold and both the ultimate tensile strength (UTS) and modulus by more than three-fold compared with normoxic (20% oxygen tension), noninsulin supplemented controls. In addition, collagen deposited on a per-cell basis increased by approximately four-fold. Interaction was demonstrated for hypoxia and insulin in combination in terms of UTS and collagen production on a per-cell basis. This interaction resulted from two distinct processes involved in collagen fibril formation. Western blot analysis showed that insulin supplementation alone increased Akt phosphorylation and the combined treatment increased collagen prolyl-4-hydroxylase. These molecules are distinct regulators of collagen deposition, having an impact at both the transcriptional and posttranslational modification stages of collagen fibril formation that, in turn, increase collagen density in the tissue constructs. These findings highlight the potential of utilizing insulin supplementation and hypoxic culture in combination to increase the mechanical strength and stiffness of fibrin-based engineered tissues.
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http://dx.doi.org/10.1089/ten.TEA.2011.0017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313606PMC
April 2012

Shear stress responses of adult blood outgrowth endothelial cells seeded on bioartificial tissue.

Tissue Eng Part A 2011 Oct 1;17(19-20):2511-21. Epub 2011 Jul 1.

Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.

Human blood outgrowth endothelial cells (HBOECs) are expanded from circulating endothelial progenitor cells in peripheral blood and thus could provide a source of autologous endothelial cells for tissue-engineered vascular grafts. To examine the suitability of adult HBOECs for use in vascular tissue engineering, the shear stress responsiveness of these cells was examined on bioartificial tissue formed from dermal fibroblasts entrapped in tubular fibrin gels. HBOECs adhered to this surface, deposited collagen IV and laminin, and remained adherent when exposed to 15 dyn/cm(2) shear stress for 24 h. The shear stress responses of HBOECs were compared to human umbilical vein endothelial cells (HUVECs). As with HUVECs, HBOECs upregulated vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 when exposed to tumor necrosis factor (TNF)-α and shear stress decreased the expression of these adhesion molecules on TNF-α-activated monolayers. Nitric oxide production was elevated by shear stress, but did not vary between cell types. Both cell types decreased platelet adhesion to the bioartificial tissue, whereas pre-exposing the cells to flow decreased platelet adhesion further. These results illustrate the potential utility for HBOECs in vascular tissue engineering, as not only do the cells adhere to bioartificial tissue and remain adherent under physiological shear stress, they are also responsive to shear stress signaling.
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http://dx.doi.org/10.1089/ten.TEA.2011.0055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179622PMC
October 2011

Ruthenium-catalyzed photo cross-linking of fibrin-based engineered tissue.

Biomaterials 2011 Apr 31;32(10):2479-88. Epub 2010 Dec 31.

Department of Biomedical Engineering, University of Minnesota, 7-105 Nils Hasselmo Hall, 312 Church St., Minneapolis, MN 55455, United States.

Most cross-linking methods utilize chemistry or physical processes that are detrimental to cells and tissue development. Those that are not as harmful often do not provide a level of strength that ultimately meets the required application. The purpose of this work was to investigate the use of a ruthenium-sodium persulfate cross-linking system to form dityrosine in fibrin-based engineered tissue. By utilizing the tyrosine residues inherent to fibrin and cell-deposited proteins, at least 3-fold mechanical strength increases and 10-fold stiffness increases were achieved after cross-linking. This strengthening and stiffening effect was found to increase with culture duration prior to cross-linking such that physiologically relevant properties were obtained. Fibrin was not required for this effect as demonstrated by testing with collagen-based engineered tissue. Cross-linked tissues were implanted subcutaneously and shown to have minimal inflammation after 30 days, similar to non-cross-linked controls. Overall, the method employed is rapid, non-toxic, minimally inflammatory, and is capable of increasing strength and stiffness of engineered tissues to physiological levels.
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http://dx.doi.org/10.1016/j.biomaterials.2010.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791330PMC
April 2011

Fibrin degradation enhances vascular smooth muscle cell proliferation and matrix deposition in fibrin-based tissue constructs fabricated in vitro.

Tissue Eng Part A 2010 Oct;16(10):3261-70

Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.

Completely biological tissue replacements can be fabricated by entrapping cells in a molded fibrin gel. Over time, the fibrin is degraded and replaced with cell-produced extracellular matrix. However, the relationship between fibrin degradation and matrix deposition has not been elucidated. We developed techniques to quantify fibrin degradation products (FDP) and examine plasmin activity in the conditioned medium from fibrin-based constructs. Fibrin-based tissue constructs fabricated with vascular smooth muscle cells (vSMC) were cultured for 5 weeks in the presence of varied concentrations of the fibrinolysis inhibitor -aminocaproic acid and cellularity, and deposited collagen and elastin were measured weekly. These data revealed that increasing concentrations of -aminocaproic acid led to delayed and diminished FDP production, lower vSMC proliferation, and decreased collagen and elastin deposition. FDP were shown to have a direct biological effect on vSMC cultures and vSMC within the fibrin-based constructs. Supplementing construct cultures with 250 or 500μg/mL FDP led to 30% higher collagen deposition than the untreated controls. FDP concentrations as high as 250μg/mL were estimated to exist within the constructs, indicating that FDP generation during remodeling of the fibrin-based constructs exerted direct biological activity. These results help explain many of the positive outcomes reported with fibrin-based tissue constructs in the literature, as well as demonstrate the importance of regulating plasmin activity during their fabrication.
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http://dx.doi.org/10.1089/ten.tea.2009.0708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947425PMC
October 2010

Functional tissue-engineered valves from cell-remodeled fibrin with commissural alignment of cell-produced collagen.

Tissue Eng Part A 2008 Jan;14(1):83-95

Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.

Heart valve replacements composed of living tissue that can adapt, repair, and grow with a patient would provide a more clinically beneficial option than current inert replacements. Bioartificial valves were produced by entrapping human dermal fibroblasts within a fibrin gel. Using a mold design that presents appropriate mechanical constraints to the cell-induced fibrin gel compaction, gross fiber alignment (commissure-to-commissure alignment in the leaflets and circumferential alignment in the root) and the basic geometry of a native aortic valve were obtained. After static incubation on the mold in complete medium supplemented with transforming growth factor beta 1, insulin, and ascorbate, collagen fibers produced by the entrapped cells were found to coalign with the fibrin based on histological analyses. The resultant tensile mechanical properties were anisotropic. Ultimate tensile strength and tensile modulus of the leaflets in the commissural direction were 0.53 and 2.34 MPa, respectively. The constructs were capable of withstanding backpressure commensurate with porcine aortic valves in regurgitation tests (330 mmHg) and opened and closed under physiological pressure swings of 10 and 20 mmHg, respectively. These data support proof of principle of using cell-remodeled fibrin gel to produce tissue-engineered valve replacements.
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http://dx.doi.org/10.1089/ten.a.2007.0148DOI Listing
January 2008

Construction and characterization of a highly redundant Pseudomonas aeruginosa genomic library prepared from 12 clinical isolates: application to studies of gene distribution among populations.

Int J Pediatr Otorhinolaryngol 2006 Nov 8;70(11):1891-900. Epub 2006 Aug 8.

Center for Genomic Sciences, Allegheny-Singer Research Institute, 320 E. North Avenue, Pittsburgh, PA 15212, United States.

Objective: To create, array, and characterize a pooled, high-coverage, genomic library composed of multiple biofilm-forming clinical strains of the opportunistic pathogen, Pseudomonas aeruginosa (PA). Twelve strains were obtained from patients with otorrhea, otitis media, and cystic fibrosis as a resource for investigating: difference in the transcriptomes of planktonic and biofilm envirovars; the size of the PA supragenome and determining the number of virulence genes available at the population level; and the distributed genome hypothesis.

Methods: High molecular weight genomic DNAs from 12 clinical PA strains were individually hydrodynamically sheared to produce mean fragment sizes of approximately 1.5 kb. Equimolar amounts of the 12 sheared genomic DNAs were then pooled and used in the construction of a genomic library with approximately 250,000 clones that was arrayed and subjected to quality control analyses.

Results: Restriction endonuclease and sequence analyses of 686 clones picked at random from the library demonstrated that >75% of the clones contained inserts larger than 0.5 kb with the desired mean insert size of 1.4 kb. Thus, this library provides better than 4.5x coverage for each of the genomes from the 12 components clinical PA isolates. Our sequencing effort ( approximately 1 million nucleotides to date) reveals that 13% of the clones present in this library are not represented in the genome of the reference P. aeruginosa strain PA01.

Conclusions: Our data suggests that reliance on a single laboratory strain, such as PA01, as being representative of a pathogenic bacterial species will fail to identify many important genes, and that to obtain a complete picture of complex phenomena, including bacterial pathogenesis and the genetics of biofilm development will require characterization of the P. aeruginosa population-based supra-genome.
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http://dx.doi.org/10.1016/j.ijporl.2006.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1635782PMC
November 2006

Cell sourcing and culture conditions for fibrin-based valve constructs.

Tissue Eng 2006 Jun;12(6):1489-502

Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA.

Cell sourcing for tissue-engineered heart valves remains a critical issue. In this work, human dermal fibroblasts (HDF) or porcine valve interstitial cells (PVIC) were entrapped in adherent fibrin disk constructs and harvested at 3 and 5 weeks. We compared the fibrin remodeling abilities of each cell type in Dulbecco's Modified Eagle's Medium (DMEM) and DMEM/F12 supplemented with transforming growth factor beta (TGF), and the response of PVIC to DMEM/F12 supplemented with fibroblast growth factor (FGF), a combination of FGF and TGF, and TGF with varying ascorbic acid (AA) concentrations. Culture media were supplemented with serum, insulin, AA, a fibrinolysis inhibitor, and antibiotics. DMEM maximized collagen and elastin deposition by HDF, while DMEM/F12 with FGF yielded the highest fibrin remodeling response by PVIC. HDF degraded fibrin slower than PVIC, and PVIC constructs had higher cellularity than HDF constructs in DMEM and DMEM/F12 at 3 weeks. FGF addition increased collagen content, collagen deposited per cell, and collagen as percentage of total protein compared to medium supplemented with TGF or TGF and FGF. AA addition increased collagen deposition by PVIC, but there was no dose dependence between 50 and 150 microg/mL AA. These results collectively show that PVIC are able to remodel fibrin faster and exhibit greater mechanical stiffening compared to HDF. Conditions for increased collagen deposition are also identified toward the engineering of valve constructs.
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http://dx.doi.org/10.1089/ten.2006.12.1489DOI Listing
June 2006

Supervision of residents by faculty radiologists using home workstations.

Emerg Radiol 2003 Dec 29;10(3):121-5. Epub 2003 Aug 29.

Our purpose was to determine if a home-based faculty radiologist equipped with a high-resolution workstation could add new information to residents' readings on overnight computed chest images that was equivalent to the new information generated by faculty reviewers inside the hospital. Teleconferencing software was installed on home workstations for online supervision of residents by faculty on chest images from a cardiothoracic intensive care unit. Critical observations that could affect patient care were recorded by first-year radiology residents before and after teleconferencing with the home-based radiologist. The amount of information added was compared with that which was added on the same 50 images through direct consultations with faculty inside the medical center. The amount of critical information that was added by teleconferencing with a chest radiologist at home was equivalent statistically to the information added through direct supervision of residents by faculty inside the hospital. Teleconferencing resulted in 149 changes in critical image findings as reported initially by the residents, out of 800 possible findings on 50 chest images, as opposed to 142 changes in residents' readings by faculty inside the medical center. Faculty subspecialists can supervise radiology residents effectively from their homes after hours, using high-resolution workstations and special teleconferencing software.
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http://dx.doi.org/10.1007/s10140-003-0283-6DOI Listing
December 2003

Interfibrillar collagen bonding exists in matrix produced by chondrocytes in culture: evidence by electron microscopy.

Tissue Eng 2002 Dec;8(6):989-95

Department of Orthopedic Surgery, University of Minnesota, Minneapolis, Minnesota 55455, USA.

Interfibrillar bonding of collagen fibrils in tissue grown from rabbit chondrocytes in culture was examined by a variety of electron microscopy techniques. Interfibrillar bonding is expected to increase tissue strength and may be a desirable feature in engineered cartilage and other soft tissues. The apparent bonding evident by scanning electron microscopy, using standard chemical fixation processing, is suspected to be artifact due to drying. The goal of this article was to establish the existence of interfibrillar bonding, apart from any processing artifacts. Specimens prepared by transmission electron microscopy, scanning electron microscopy (SEM) after notching and fixing under load, and cryo-SEM all showed evidence of bonding, supporting the existence of bonding in the unprocessed tissue. Exclusion from the bond space of gold particles labeled to decorin further supported the existence of natural bonds. Artifactual bonding may still be occurring with some of the methods used, but interfibrillar bonds exist in natural tissue. The bond distance was estimated to be 7-14 nm. Demonstration of the existence of these bonds supports further study of their mechanism and effect on tissue properties.
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http://dx.doi.org/10.1089/107632702320934083DOI Listing
December 2002

Prostaglandins and the Zone of Calcified Cartilage in Osteoarthritis.

Am J Ther 1996 Feb;3(2):139-149

Departments of Orthopaedic Surgery and Biochemistry, University of Minnesota, Minneapolis, USA.

The zone of calcified cartilage (ZCC) which provides the critical interface between cartilage and bone acts as the growth plate in the developing joint. In osteoarthritis, it has been hypothesized that the ZCC may again function in joint remodeling. This could result in thinning of the cartilage. This report is the first experimental confirmation of this hypothesis. Osteoarthritis was induced using the Hulth procedure in 2.3--2.7-kg rabbits. Approximately 3 weeks after surgery, half of the menisectomy rabbits and half of the nonmenisectomy rabbits were given 20 &mgr;g of misoprostol interarticularly for 5 days per week for 2.5 weeks. In the patellae and tibial plateau, the rate of movement of the tidemark of the ZCC was measured. Medial aspect femoral condyle cartilage was incubated in the presence of [(35)S]sulfate and [(3)H]proline. After menisectomy, rate of movement of the ZCC was dramatically increased and was unchanged by misoprostol. Proteoglycan synthesis was highly elevated in the osteoarthritis-induced knees, and misoprostol suppressed the rate of [(35)S]sulfate but not [(3)H]proline incorporation.
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http://dx.doi.org/10.1097/00045391-199602000-00008DOI Listing
February 1996