From New England Journal of Medicine
Vicente E. Torres, M.D., Ph.D., Arlene B. Chapman, M.D., Olivier Devuyst, M.D., Ph.D., Ron T. Gansevoort, M.D., Ph.D., Ronald D. Perrone, M.D., Gary Koch, Ph.D., John Ouyang, Ph.D., Robert D. McQuade, Ph.D., Jaime D. Blais, Ph.D., Frank S. Czerwiec, M.D., Ph.D., and Olga Sergeyeva, M.D., M.P.H., for the REPRISE Trial Investigators*
November 4, 2017DOI: 10.1056/NEJMoa1710030
Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease
Autosomal dominant polycystic kidney disease (ADPKD) is the fourth leading cause of end-stage kidney disease in adults.1-3 When the genes encoding polycystin 1 (PKD1) and polycystin 2 (PKD2) are disrupted, tubular epithelial cells in vasopressin-sensitive distal nephrons and collecting ducts show enhanced proliferation, chloride-driven fluid secretion, and expression of proinflammatory cytokines, resulting in cyst development and the destruction of renal parenchyma.4
Vasopressin promotes kidney-cyst cell proliferation and fluid secretion by means of up-regulation of adenosine-3′,5′-cyclic monophosphate (cAMP).5,6 The suppression of vasopressin production, release, or action by means of hydration,7,8 V2-receptor blockade,9-14 or genetic mutation15 has been shown to reduce cyst burden, protect kidney function, and prolong survival in rodent models.
In the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 trial, which involved patients with early ADPKD (estimated creatinine clearance, ≥60 ml per minute), tolvaptan reduced kidney growth and the decline in the estimated glomerular filtration rate (GFR).16 The benefit with regard to the estimated GFR was maintained after 2 additional years of open-label treatment (TEMPO 4:4 study).17 Idiosyncratic hepatocellular toxic effects were unanticipated.18 With monitoring occurring once every 4 months, two patients in the TEMPO 3:4 trial and one in the TEMPO 4:4 study had evidence of potentially serious drug-induced liver injury. We conducted the Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trial, a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial involving patients with ADPKD who had late chronic kidney disease of stage 2 to early stage 4, in order to ascertain the efficacy and safety of tolvaptan in patients with more advanced ADPKD with the use of more frequent monitoring for toxic effects in the liver.19
METHODS
Trial Design and Oversight
The institutional review board at each site approved the protocol and the informed-consent form. A steering committee that comprised investigators and representatives of the sponsor (Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization) oversaw the trial design and conduct with the assistance of an independent data and safety monitoring committee and a hepatic adjudication committee. The sponsor collected and analyzed the data. The first author wrote the manuscript with substantial contributions from the coauthors (including authors who are employees of the sponsor) and assumes responsibility for its content and integrity. The sponsor had no other role in writing or reviewing the manuscript. All the authors had access to the analyzed data, jointly decided to submit the manuscript for publication, and vouch for the accuracy and completeness of the reported data and for fidelity of the trial to the protocol. The trial protocol, which is available with the full text of this article at NEJM.org, has been published previously.19
From May 2014 through March 2016, patients were enrolled at 213 sites globally. Eligible persons were either 18 to 55 years of age with an estimated GFR of 25 to 65 ml per minute per 1.73 m2 of body-surface area or 56 to 65 years of age with an estimated GFR of 25 to 44 ml per minute per 1.73 m2. Patients in the older age group also had to have historical evidence of a decline in the estimated GFR of more than 2.0 ml per minute per 1.73 m2 per year.20
The trial consisted of an 8-week prerandomization period that was divided into a screening phase, a single-blind placebo run-in phase, and a single-blind tolvaptan period that comprised a dose-adjustment phase and a run-in phase (Fig. S1 in the Supplementary Appendix, available at NEJM.org). Patients who could take tolvaptan at daily morning and afternoon doses of 60 mg and 30 mg, respectively, or 90 mg and 30 mg, respectively, were randomly assigned in a 1:1 ratio, in a double-blind fashion, to receive tolvaptan or matching placebo for 12 months. Randomization was stratified according to the baseline estimated GFR (≤45 or >45 ml per minute per 1.73 m2), age of the patient (≤55 or >55 years), and total kidney volume (≤2000 ml, >2000 ml, or unknown).21 The maximal dose of tolvaptan that could be taken without an unacceptable level of side effects during the run-in period, or the equivalent as matching placebo, was dispensed according to the randomization assignment. Adjustment of the dose down to morning and afternoon doses of 45 mg and 15 mg, respectively, or of 30 mg and 15 mg, respectively, was permitted during the trial period.
Serum creatinine levels were measured centrally with the use of the isotope dilution mass spectrometry–traceable enzymatic method and were reported to two decimal points.19,22Determinations of the estimated GFR were made with the use of the Chronic Kidney Disease Epidemiology Collaboration equation.23
Trial Assessments
Evaluations were performed at baseline (during the screening and placebo run-in phases) and during the single-blind tolvaptan period (Fig. S1 in the Supplementary Appendix). Patients underwent monthly laboratory testing and reported to the trial sites every 3 months. Three follow-up laboratory visits occurred between days 7 and 40 after the receipt of the last dose of the assigned trial regimen. For patients who did not complete the trial, the follow-up period started after the discontinuation of the trial regimen and included a final follow-up at the originally scheduled 12-month visit.
Outcome Measures
Primary End Point
The primary end point was the change in the estimated GFR from baseline (before the receipt of any placebo or tolvaptan) to follow-up (after the 1-year trial period had been completed), with adjustment for the time each patient was in the trial and with interpolation to 1 year. Without this adjustment, the trial group that had more withdrawals or earlier withdrawals would have had an advantage because patients who withdrew early would have had less time for renal-function deterioration. The GFR values that were obtained before and after the receipt of any placebo or tolvaptan were estimated from the mean of three baseline serum creatinine values (two obtained during screening and one during the placebo run-in phase) and from the mean of three follow-up values that were obtained after the 1-year trial period was completed. The trial duration for each patient was defined as the interval between the median timings of the baseline observations and the follow-up observations. These estimated GFR measurements were not affected by the acute hemodynamic effect of tolvaptan, which is rapidly reversible when the drug is not being taken.24-26Vasopressin acting on V2-receptors increases the glomerular filtration rate by means of the activation of tubuloglomerular feedback and afferent vasodilation and by means of renin release and efferent vasoconstriction27,28; tolvaptan counteracts these effects. [Read more]
From Business Wire
Palladio Biosciences Announces Presentations of New Data for Lixivaptan and Polycystic Kidney Disease during the American Society of Nephrology 2017 Annual Meeting
Palladio Biosciences, Inc. (Palladio) http://palladiobio.com/, a privately held biopharmaceutical company founded to develop medicines that make a meaningful impact on the lives of patients with orphan diseases of the kidney, today announced that new data for lixivaptan for the treatment of polycystic kidney disease (PKD) will be presented in two poster sessions during the American Society of Nephrology 2017 annual meeting, to be held in New Orleans, LA on November 2-5.
Briefly, the first poster presents results of an experiment that investigated the effect of lixivaptan in the PCK rat, a validated, orthologous animal model of human PKD. In this study, a beneficial effect of lixivaptan was observed consistently across all aspects of disease tested, including biochemical markers, renal morphology, and renal function.
In the second presentation, data from a large body of existing clinical and preclinical work were used to evaluate whether lixivaptan has safety and efficacy characteristics that suggest a favorable risk-benefit profile for the treatment of Autosomal Dominant Kidney Disease (ADPKD). To explore efficacy, the effect of lixivaptan on accepted pharmacodynamic markers of efficacy in ADPKD was investigated. To explore safety, a DILIsym simulation, a predictive, multiscale computational model of drug-induced liver injury, was conducted to assess the potential for hepatocellular injury compared to tolvaptan. Results supported the potential efficacy of lixivaptan for ADPKD and indicated that lixivaptan was not associated with hepatocellular toxicity at doses expected for ADPKD. Lixivaptan thus has the potential to become a safe and effective therapy for the treatment of ADPKD in a broad patient population.
Details for the accepted poster abstracts are listed below. They can be accessed online on the conference website at: https://www.asn-online.org/education/kidneyweek/2017/program-search-abstract.aspx
Effects of a Novel Vasopressin V2 Receptor Antagonist on Cystic Disease Progression in the PCK Rat
Poster Number: TH-PO574
Presentation date/time: November 02, 2017 / 10:00 AM – 12:00 PM
Location: Hall G
Lixivaptan, a Novel Vasopressin V2 Receptor Antagonist in Development for the Treatment of Autosomal Dominant Polycystic Kidney Disease
Poster Number: FR-PO326
Presentation date/time: November 03, 2017 / 10:00 AM – 12:00 PM
Location: Hall G
About Lixivaptan:
Lixivaptan was granted orphan designation by FDA for the treatment of ADPKD. It is a potent, selective vasopressin V2 receptor antagonist, a mechanism of action that has clinical proof of concept to delay the progression of ADPKD. Lixivaptan was previously administered to 1,673 subjects across 36 clinical studies as part of a prior clinical development program for the treatment of hyponatremia. Palladio expects to leverage lixivaptan’s large body of data generated in the hyponatremia clinical program to repurpose lixivaptan and advance its development for the treatment of ADPKD.
New tissue-engineered blood vessel replacements one step closer to human trials
Researchers at the University of Minnesota have created a new lab-grown blood vessel replacement that is the first-of-its-kind nonsynthetic, decellularized graft that becomes repopulated with cells by the recipient's own cells when implanted. Credit: University of Minnesota
Researchers at the University of Minnesota have created a new lab-grown blood vessel replacement that is composed completely of biological materials, but surprisingly doesn't contain any living cells at implantation. The vessel, that could be used as an "off the shelf" graft for kidney dialysis patients, performed well in a recent study with nonhuman primates.
It is the first-of-its-kind nonsynthetic, decellularized graft that becomes repopulated with cells by the recipient's own cells when implanted. The discovery could help tens of thousands of kidney dialysis patients each year. The grafts could also be adapted in the future for use as coronary and peripheral bybass blood vessels and tubular heart valves.
The research was published today as the cover story in Science Translational Medicine. The University of Minnesota has also licensed the technology.
More than 100,000 people in the United States begin hemodialysis each year to treat kidney disease and more than 400,000 people are being treated with life-saving hemodialysis nationwide, according to the U.S. Renal Data System Annual Data Report. An arteriovenous fistula, which connects an artery to a vein in the arm, is currently the preferred mode of blood vessel access for hemodialysis. However, 30-50 percent of patients experience complications and need to connect the vein and artery using an artificial tube, called an arteriovenous graft.
Currently, these artificial grafts are made of synthetic materials that are prone to clotting, infection and other complications. Grafts grown in the lab from cells and biological materials could cause fewer adverse reactions, but living tissues aren't stable for long-term storage and could induce an immune response unless the patient's own cells were used, both being barriers to commercialization and clinical use.
In this pre-clinical study, University of Minnesota researchers generated vessel-like tubes in the lab from post-natal human skin cells that were embedded in a gel-like material made of cow fibrin, a protein involved in blood clotting. Researchers put the cell-populated gel in a bioreactor and grew the tube for seven weeks and then washed away the cells over the final week. What remained was the collagen and other proteins secreted by the cells, making an all-natural, but non-living tube for implantation.
"We harnessed the body's normal wound-healing system in this process by starting with skin cells in a fibrin gel, which is Nature's starting point for healing," said University of Minnesota Department of Biomedical Engineering Professor Robert Tranquillo who led the study. "Washing away the cells in the final step reduces the chance of rejection. This also means the vessels can be stored and implanted when they are needed because they are no longer a living material. In the future, thousands of the lab-grown vessels could be made from a small skin biopsy from one donor and then stored on the shelf for when they are needed by patients."
To test the vessels, the researchers implanted the 15-centimeter-long (about 5 inches) lab-grown grafts into adult baboons donated by Mayo Clinic as it was closing down its primate facility. Six months after implantation, the grafts grossly appeared like a blood vessel and the researchers observed healthy cells from the recipients taking up residence within the walls of the tubes. None of the grafts calcified and only one ruptured, which was attributed to inadvertent mechanical damage with handling. The grafts after six months were shown to withstand almost 30 times the average human blood pressure without bursting. The implants showed no immune response and resisted infection. In addition, the grafts withstood repeated needle punctures by self-healing, which would be a necessary process for patients undergoing long-term dialysis.
"This pre-clinical trial was extremely important to us," Tranquillo said. "In previous studies, we implanted vessels in sheep, but we needed to test them in a more human-like model before risking human lives because the success of our material depends on the ability of the recipient to recellularize it into a living tissue without immune response, which might have failed in a human even though it succeeded in a sheep."
With the success of this study, Tranquillo and the team will seek FDA approval for clinical trials in children with pediatric heart defects since they recently reported a study in Nature Communications that this material is also capable of growing.
Vasopressin promotes kidney-cyst cell proliferation and fluid secretion by means of up-regulation of adenosine-3′,5′-cyclic monophosphate (cAMP).5,6 The suppression of vasopressin production, release, or action by means of hydration,7,8 V2-receptor blockade,9-14 or genetic mutation15 has been shown to reduce cyst burden, protect kidney function, and prolong survival in rodent models.
In the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 trial, which involved patients with early ADPKD (estimated creatinine clearance, ≥60 ml per minute), tolvaptan reduced kidney growth and the decline in the estimated glomerular filtration rate (GFR).16 The benefit with regard to the estimated GFR was maintained after 2 additional years of open-label treatment (TEMPO 4:4 study).17 Idiosyncratic hepatocellular toxic effects were unanticipated.18 With monitoring occurring once every 4 months, two patients in the TEMPO 3:4 trial and one in the TEMPO 4:4 study had evidence of potentially serious drug-induced liver injury. We conducted the Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trial, a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial involving patients with ADPKD who had late chronic kidney disease of stage 2 to early stage 4, in order to ascertain the efficacy and safety of tolvaptan in patients with more advanced ADPKD with the use of more frequent monitoring for toxic effects in the liver.19
METHODS
Trial Design and Oversight
The institutional review board at each site approved the protocol and the informed-consent form. A steering committee that comprised investigators and representatives of the sponsor (Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization) oversaw the trial design and conduct with the assistance of an independent data and safety monitoring committee and a hepatic adjudication committee. The sponsor collected and analyzed the data. The first author wrote the manuscript with substantial contributions from the coauthors (including authors who are employees of the sponsor) and assumes responsibility for its content and integrity. The sponsor had no other role in writing or reviewing the manuscript. All the authors had access to the analyzed data, jointly decided to submit the manuscript for publication, and vouch for the accuracy and completeness of the reported data and for fidelity of the trial to the protocol. The trial protocol, which is available with the full text of this article at NEJM.org, has been published previously.19
From May 2014 through March 2016, patients were enrolled at 213 sites globally. Eligible persons were either 18 to 55 years of age with an estimated GFR of 25 to 65 ml per minute per 1.73 m2 of body-surface area or 56 to 65 years of age with an estimated GFR of 25 to 44 ml per minute per 1.73 m2. Patients in the older age group also had to have historical evidence of a decline in the estimated GFR of more than 2.0 ml per minute per 1.73 m2 per year.20
The trial consisted of an 8-week prerandomization period that was divided into a screening phase, a single-blind placebo run-in phase, and a single-blind tolvaptan period that comprised a dose-adjustment phase and a run-in phase (Fig. S1 in the Supplementary Appendix, available at NEJM.org). Patients who could take tolvaptan at daily morning and afternoon doses of 60 mg and 30 mg, respectively, or 90 mg and 30 mg, respectively, were randomly assigned in a 1:1 ratio, in a double-blind fashion, to receive tolvaptan or matching placebo for 12 months. Randomization was stratified according to the baseline estimated GFR (≤45 or >45 ml per minute per 1.73 m2), age of the patient (≤55 or >55 years), and total kidney volume (≤2000 ml, >2000 ml, or unknown).21 The maximal dose of tolvaptan that could be taken without an unacceptable level of side effects during the run-in period, or the equivalent as matching placebo, was dispensed according to the randomization assignment. Adjustment of the dose down to morning and afternoon doses of 45 mg and 15 mg, respectively, or of 30 mg and 15 mg, respectively, was permitted during the trial period.
Serum creatinine levels were measured centrally with the use of the isotope dilution mass spectrometry–traceable enzymatic method and were reported to two decimal points.19,22Determinations of the estimated GFR were made with the use of the Chronic Kidney Disease Epidemiology Collaboration equation.23
Trial Assessments
Evaluations were performed at baseline (during the screening and placebo run-in phases) and during the single-blind tolvaptan period (Fig. S1 in the Supplementary Appendix). Patients underwent monthly laboratory testing and reported to the trial sites every 3 months. Three follow-up laboratory visits occurred between days 7 and 40 after the receipt of the last dose of the assigned trial regimen. For patients who did not complete the trial, the follow-up period started after the discontinuation of the trial regimen and included a final follow-up at the originally scheduled 12-month visit.
Outcome Measures
Primary End Point
The primary end point was the change in the estimated GFR from baseline (before the receipt of any placebo or tolvaptan) to follow-up (after the 1-year trial period had been completed), with adjustment for the time each patient was in the trial and with interpolation to 1 year. Without this adjustment, the trial group that had more withdrawals or earlier withdrawals would have had an advantage because patients who withdrew early would have had less time for renal-function deterioration. The GFR values that were obtained before and after the receipt of any placebo or tolvaptan were estimated from the mean of three baseline serum creatinine values (two obtained during screening and one during the placebo run-in phase) and from the mean of three follow-up values that were obtained after the 1-year trial period was completed. The trial duration for each patient was defined as the interval between the median timings of the baseline observations and the follow-up observations. These estimated GFR measurements were not affected by the acute hemodynamic effect of tolvaptan, which is rapidly reversible when the drug is not being taken.24-26Vasopressin acting on V2-receptors increases the glomerular filtration rate by means of the activation of tubuloglomerular feedback and afferent vasodilation and by means of renin release and efferent vasoconstriction27,28; tolvaptan counteracts these effects. [Read more]
From Business Wire
Palladio Biosciences Announces Presentations of New Data for Lixivaptan and Polycystic Kidney Disease during the American Society of Nephrology 2017 Annual Meeting
Palladio Biosciences, Inc. (Palladio) http://palladiobio.com/, a privately held biopharmaceutical company founded to develop medicines that make a meaningful impact on the lives of patients with orphan diseases of the kidney, today announced that new data for lixivaptan for the treatment of polycystic kidney disease (PKD) will be presented in two poster sessions during the American Society of Nephrology 2017 annual meeting, to be held in New Orleans, LA on November 2-5.
Briefly, the first poster presents results of an experiment that investigated the effect of lixivaptan in the PCK rat, a validated, orthologous animal model of human PKD. In this study, a beneficial effect of lixivaptan was observed consistently across all aspects of disease tested, including biochemical markers, renal morphology, and renal function.
In the second presentation, data from a large body of existing clinical and preclinical work were used to evaluate whether lixivaptan has safety and efficacy characteristics that suggest a favorable risk-benefit profile for the treatment of Autosomal Dominant Kidney Disease (ADPKD). To explore efficacy, the effect of lixivaptan on accepted pharmacodynamic markers of efficacy in ADPKD was investigated. To explore safety, a DILIsym simulation, a predictive, multiscale computational model of drug-induced liver injury, was conducted to assess the potential for hepatocellular injury compared to tolvaptan. Results supported the potential efficacy of lixivaptan for ADPKD and indicated that lixivaptan was not associated with hepatocellular toxicity at doses expected for ADPKD. Lixivaptan thus has the potential to become a safe and effective therapy for the treatment of ADPKD in a broad patient population.
Details for the accepted poster abstracts are listed below. They can be accessed online on the conference website at: https://www.asn-online.org/education/kidneyweek/2017/program-search-abstract.aspx
Effects of a Novel Vasopressin V2 Receptor Antagonist on Cystic Disease Progression in the PCK Rat
Poster Number: TH-PO574
Presentation date/time: November 02, 2017 / 10:00 AM – 12:00 PM
Location: Hall G
Lixivaptan, a Novel Vasopressin V2 Receptor Antagonist in Development for the Treatment of Autosomal Dominant Polycystic Kidney Disease
Poster Number: FR-PO326
Presentation date/time: November 03, 2017 / 10:00 AM – 12:00 PM
Location: Hall G
About Lixivaptan:
Lixivaptan was granted orphan designation by FDA for the treatment of ADPKD. It is a potent, selective vasopressin V2 receptor antagonist, a mechanism of action that has clinical proof of concept to delay the progression of ADPKD. Lixivaptan was previously administered to 1,673 subjects across 36 clinical studies as part of a prior clinical development program for the treatment of hyponatremia. Palladio expects to leverage lixivaptan’s large body of data generated in the hyponatremia clinical program to repurpose lixivaptan and advance its development for the treatment of ADPKD.
From MedicalXpress
Researchers at the University of Minnesota have created a new lab-grown blood vessel replacement that is the first-of-its-kind nonsynthetic, decellularized graft that becomes repopulated with cells by the recipient's own cells when implanted. Credit: University of Minnesota
It is the first-of-its-kind nonsynthetic, decellularized graft that becomes repopulated with cells by the recipient's own cells when implanted. The discovery could help tens of thousands of kidney dialysis patients each year. The grafts could also be adapted in the future for use as coronary and peripheral bybass blood vessels and tubular heart valves.
The research was published today as the cover story in Science Translational Medicine. The University of Minnesota has also licensed the technology.
More than 100,000 people in the United States begin hemodialysis each year to treat kidney disease and more than 400,000 people are being treated with life-saving hemodialysis nationwide, according to the U.S. Renal Data System Annual Data Report. An arteriovenous fistula, which connects an artery to a vein in the arm, is currently the preferred mode of blood vessel access for hemodialysis. However, 30-50 percent of patients experience complications and need to connect the vein and artery using an artificial tube, called an arteriovenous graft.
Currently, these artificial grafts are made of synthetic materials that are prone to clotting, infection and other complications. Grafts grown in the lab from cells and biological materials could cause fewer adverse reactions, but living tissues aren't stable for long-term storage and could induce an immune response unless the patient's own cells were used, both being barriers to commercialization and clinical use.
In this pre-clinical study, University of Minnesota researchers generated vessel-like tubes in the lab from post-natal human skin cells that were embedded in a gel-like material made of cow fibrin, a protein involved in blood clotting. Researchers put the cell-populated gel in a bioreactor and grew the tube for seven weeks and then washed away the cells over the final week. What remained was the collagen and other proteins secreted by the cells, making an all-natural, but non-living tube for implantation.
"We harnessed the body's normal wound-healing system in this process by starting with skin cells in a fibrin gel, which is Nature's starting point for healing," said University of Minnesota Department of Biomedical Engineering Professor Robert Tranquillo who led the study. "Washing away the cells in the final step reduces the chance of rejection. This also means the vessels can be stored and implanted when they are needed because they are no longer a living material. In the future, thousands of the lab-grown vessels could be made from a small skin biopsy from one donor and then stored on the shelf for when they are needed by patients."
To test the vessels, the researchers implanted the 15-centimeter-long (about 5 inches) lab-grown grafts into adult baboons donated by Mayo Clinic as it was closing down its primate facility. Six months after implantation, the grafts grossly appeared like a blood vessel and the researchers observed healthy cells from the recipients taking up residence within the walls of the tubes. None of the grafts calcified and only one ruptured, which was attributed to inadvertent mechanical damage with handling. The grafts after six months were shown to withstand almost 30 times the average human blood pressure without bursting. The implants showed no immune response and resisted infection. In addition, the grafts withstood repeated needle punctures by self-healing, which would be a necessary process for patients undergoing long-term dialysis.
"This pre-clinical trial was extremely important to us," Tranquillo said. "In previous studies, we implanted vessels in sheep, but we needed to test them in a more human-like model before risking human lives because the success of our material depends on the ability of the recipient to recellularize it into a living tissue without immune response, which might have failed in a human even though it succeeded in a sheep."
With the success of this study, Tranquillo and the team will seek FDA approval for clinical trials in children with pediatric heart defects since they recently reported a study in Nature Communications that this material is also capable of growing.
Amazed about the research of new tissue-engineered blood vessel replacements has to be successful ..Latest Tamilnadu State Politics News
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