User login
Bioengineered tissues are showing promise in the treatment of valvular heart disease, according to the results of several early clinical and preclinical studies demonstrating the benefits of using heterologous substrates as scaffolding capable of promoting in vivo cell infiltration and remodeling.
Ultimately, cardiac tissue engineering seeks to develop the ideal material for replacement and repair of a variety of heart components – a material able to integrate, function, and, when necessary, grow and develop in a manner undifferentiated from normal cellular structures.
One of the most important areas of focus for such efforts is the development of heart valves and valve patches suitable for use in replacement or repair. The need is obvious: “The fact that literature continues to be published debating the best type of valve prosthesis is proof that, to date, the ideal valve substitute has not been found,” according to Cristian Rosu, Ph.D. and Dr. Edward G. Soltesz of the Cleveland Clinic (Semin Thorac Cardiovasc Surg. 2015 June 30 [doi: 10.1053/j.semtcvs.2015.06.007]).
Dr. Roşu and Dr. Soltesz go on to say that this lack of an ideal prosthetic heart valve leaves surgeons and their patients with a difficult choice at the time of valve surgery. The focus of their concern relates to how current bioprostheses are being used in younger and younger patients, and how these devices have a finite lifespan – requiring eventual reoperation and replacement, perhaps multiple times. In addition, calcification is a prominent and well-known risk of bioprosthetic valves, especially in children (Circulation. 2014 Jul 1;130[1]:51-60).
As for mechanical valves, although durable, they require a lifetime of anticoagulation therapy to prevent thrombosis. And the lack of growth potential found in both mechanical and current bioprosthetic devices is obviously a bane to pediatric valve therapy.
The latest efforts in tissue engineering therefore seek to develop valves and valve components that may be more permanent solutions by better mimicking natural valves.
But better mimicking of a natural valve is not an easy task, when such valves exist in “a near-perfect correlation of structure and function, enabling the valve to avoid excess stress on the cusps while simultaneously withstanding the wear and tear of 40-million repetitive deformations per year, equivalent to some 3 billion over a 75-year lifetime.” (“Principles of Tissue Engineering,” 4th ed. [London: Academic Press 2014, p. 813]).
The “holy grail” of tissue engineering, therefore, is to provide a completely in vitro–developed, autologous, fully cellularized, functional scaffolding for implantation that can live up to these requirements. In order to do this, extensive research into the search for the best cell sources and growth matrices and methods is underway, as illustrated by several recent reviews (Front Cell Dev Biol. 30 June 2015 [doi.org/10.3389/fcell.2015.00039] and Mater Sci Eng C. 2015 March 1;48:556-65).
Candidate cell types include a variety of embryonic stem cells, as well as adult cell types that have proven amenable to rejuvenation and redifferentiation (Adv Drug Deliv Rev. 2014;69-70:254-69).
In one example of the quest for completely in vitro human-tissue designed valves, Dr. Jean Dubé of Laval University, Quebec, and his colleagues reported research on a human tissue–engineered trileaflet heart valve assembled in vitro using human fibroblasts. These cells self-assembled into living tissue sheets when cultured in the presence of sodium ascorbate. These sheets could be layered together to create a thick construct, with the ultimate goal of replacing the use of bovine pericardium tissue implants with ones made of autologous cells from the patient (Acta Biomater. 2014 Aug;10[8]:3563-70).
Currently, however, many of the preclinical studies of fully tissue engineered heart valves have shown retraction of the heart valve leaflets as a major mechanism of functional failure. This retraction is caused by both passive and active cell stress and passive matrix stress, according to a review by Inge A.E.W. van Loosdregt, Ph.D., and her colleagues at the Eindhoven (the Netherlands) University of Technology (J Biomech. 2014 Jun 27;47[9]:2064-9).
While all of these developmental issues regarding the use of fully tissue-engineered valves are being worked out, early clinical applications are already being found for a new generation of valve prostheses that take an intermediate approach, one that uses an implanted scaffolding material that allows autologous cell infiltration and replacement in vivo.
Two of the most prominent examples of these scaffoldings currently in investigation and in early clinical use for heart valve repair or replacement are the bovine pericardium-derived CardioCel (Admedus, Brisbane, Australia) and the porcine intestinal submucosa-derived CorMatrix ECM(CorMatrix Cardiovascular, Roswell, Ga.). CorMatrix ECM was approved by the Food and Drug Administration in 2005 for pericardial repair and reconstruction, and in 2007 for cardiac tissue repair. The FDA approved CardioCel in 2014 for use in the United States in pericardial closure and for the repair of cardiac and vascular defects in both adults and children.
Both technologies rely on the concept of matrix infiltration by autologous cells after implantation in order to create a living mimic of the patient’s own tissues.
CardioCel is a highly treated, bovine pericardium-derived, decellularized collagen matrix. It showed significant resistance to calcification in mitral and pulmonary implants in a juvenile sheep model as reported by Dr. Christian P. Brizard at Royal Children’s Hospital, Melbourne, and his colleagues (J Thorac Cardiovasc Surg. 2014 Dec;148[6]:3194-201). These investigators replaced the posterior leaflet of the mitral valve and one of the pulmonary valve cusps with patches in 10-month-old ewes. They compared the use of CardioCel in six ewes to a control group of four ewes repaired with autologous pericardium that was treated intraoperatively with glutaraldehyde, which is the standard default used at their institution for more than 2 decades as the best material for valve repair in their pediatric patients.
The primary end points of the study were thickening and calcium content. They found that all animals survived with normal valve echocardiography until sacrifice at 7 months. They reported that the bovine pericardium patches allowed accurate valve repair at both systemic and pulmonary pressure with preserved mechanical properties and more-controlled healing and without calcification as compared with the controls. (Calcification is a known major risk factor for the eventual failure of bioprosthetic valves.) Additionally, the bovine pericardium patched valves showed the in vivo development of dense but thin cellularized outer layers of mature collagen I, compared with the controls, which had outer layers that were much less dense and showed the presence of immature collagen III.
In another case of valvular use of the CardioCel material, at the recent American Association for Thoracic Surgery Mitral Conclave 2015, M. Bonnie Ghosh-Dastidar, Ph.D., and her colleagues from the Royal Brompton Hospital, London, reported on a severely ill patient with significant mitral regurgitation and an infected mitral valve with large vegetations on the anterior leaflets. The infected tissue was resected and a large patch of CardioCel bovine pericardium was used to reconstruct the leaflets. Postoperative assessment showed a competent mitral valve with good area of leaflet coaptation, according to Dr. Ghosh-Dastidar.
In his invited commentary on the animal-model research by Dr. Brizard, Dr. Niv Ad, director of cardiac surgery research at Inova Heart and Vascular Institute, Falls Church, Va., said that despite the promise of the CardioCel patches, there were a number of alternative approaches being investigated. “Other engineered materials currently being study include processes such as lyophilization, which has shown promising results in reducing inflammation. Another proposed approach is the use of decellularized vessels and patches with the promise of normal remodeling and growth, such as extracellular matrix and its potential for tissue regeneration.”
Dr. Ad also stated that, “the key bioengineering challenge is to determine how biologic, structural, and mechanical factors interact and function in vivo. The understanding of these factors will prove critical to the development of a clinically viable tissue-engineered heart valve,” (J Thorac Cardiovasc Surg. 2014 Dec;148[6]:3202-3).
An example of the use of extracellular matrix material referred to by Dr. Ad is the CorMatrix ECM, which is an extracellular matrix material derived from porcine small-intestinal submucosa, processed and decellularized.
Dr. Marc W. Gerdisch and his colleagues from the Franciscan St. Francis Heart Center, Indianapolis, reported on the results of treating 19 patients with mitral valve disease using the CorMatrix patch material for partial or subtotal leaflet repair or extension. There were three deaths unrelated to the repair and no instances of perioperative or late stroke. Two patients with a history of cancer and cancer therapy experienced failure of the initial repair, requiring reintervention. However, the other mitral valve repair patients continued to show good valvular function and no calcification on echocardiographic follow-up of 4 days to 48 months (Thorac Cardiovasc Surg. 2014 Oct;148[4]:1370-8).
And in 2015, CorMatrix Cardiovascular announced FDA approval of an investigational device exemption for an early feasibility study of their CorMatrix ECM Tricuspid Heart Valve in up to 15 patients at 5 U.S. centers (NCT02397668). Indications are for the surgical management of tricuspid valve disease not amenable to annuloplasty or repair, including tricuspid valve disease secondary to congenital heart disease in pediatric patients and adult endocarditis patients. The CorMatrix ECM Tricuspid Valve is a flexible, unstented valve acting as a 3‐D scaffold designed to function immediately as a prosthetic, but one constructed to permit native cellular infiltration and remodeling.
Ultimately, both the CardioCel and the CorMatrix materials are just the tip of an iceberg of research into tissue engineering as a clinical tool. And success and the wider adoption of any current or developing technologies will require the results of far-more-extensive studies and long-term clinical results.
At some future date, engineered total organ substitutes or the routine injection of genetically engineered stem cells may provide a practical alternative for treating a diseased or damaged heart. But for now, the most-likely scenario is the continued exploration of tissue engineering to develop the most durable, growth-, stress-, and biologically compatible patches, valves, and vasculatures possible – defined tools that can be adapted to current surgical techniques, designed to obtain the best repair of congenital or acquired heart disease conditions.
As with any transformative technology in medicine, the path from laboratory success and optimistic short-term clinical results to durable, long-term postoperative benefits may be a rocky one. But given the current enthusiasm, it certainly looks as if it will be a well-traveled road.
Dr. Brizard reported consulting and lecturing fees from Admedus. His research was supported with the assistance of a grant from Admedus. Dr. Gerdisch reported consulting fees and equity ownership in CorMatrix Cardiovascular.
Bioengineered tissues are showing promise in the treatment of valvular heart disease, according to the results of several early clinical and preclinical studies demonstrating the benefits of using heterologous substrates as scaffolding capable of promoting in vivo cell infiltration and remodeling.
Ultimately, cardiac tissue engineering seeks to develop the ideal material for replacement and repair of a variety of heart components – a material able to integrate, function, and, when necessary, grow and develop in a manner undifferentiated from normal cellular structures.
One of the most important areas of focus for such efforts is the development of heart valves and valve patches suitable for use in replacement or repair. The need is obvious: “The fact that literature continues to be published debating the best type of valve prosthesis is proof that, to date, the ideal valve substitute has not been found,” according to Cristian Rosu, Ph.D. and Dr. Edward G. Soltesz of the Cleveland Clinic (Semin Thorac Cardiovasc Surg. 2015 June 30 [doi: 10.1053/j.semtcvs.2015.06.007]).
Dr. Roşu and Dr. Soltesz go on to say that this lack of an ideal prosthetic heart valve leaves surgeons and their patients with a difficult choice at the time of valve surgery. The focus of their concern relates to how current bioprostheses are being used in younger and younger patients, and how these devices have a finite lifespan – requiring eventual reoperation and replacement, perhaps multiple times. In addition, calcification is a prominent and well-known risk of bioprosthetic valves, especially in children (Circulation. 2014 Jul 1;130[1]:51-60).
As for mechanical valves, although durable, they require a lifetime of anticoagulation therapy to prevent thrombosis. And the lack of growth potential found in both mechanical and current bioprosthetic devices is obviously a bane to pediatric valve therapy.
The latest efforts in tissue engineering therefore seek to develop valves and valve components that may be more permanent solutions by better mimicking natural valves.
But better mimicking of a natural valve is not an easy task, when such valves exist in “a near-perfect correlation of structure and function, enabling the valve to avoid excess stress on the cusps while simultaneously withstanding the wear and tear of 40-million repetitive deformations per year, equivalent to some 3 billion over a 75-year lifetime.” (“Principles of Tissue Engineering,” 4th ed. [London: Academic Press 2014, p. 813]).
The “holy grail” of tissue engineering, therefore, is to provide a completely in vitro–developed, autologous, fully cellularized, functional scaffolding for implantation that can live up to these requirements. In order to do this, extensive research into the search for the best cell sources and growth matrices and methods is underway, as illustrated by several recent reviews (Front Cell Dev Biol. 30 June 2015 [doi.org/10.3389/fcell.2015.00039] and Mater Sci Eng C. 2015 March 1;48:556-65).
Candidate cell types include a variety of embryonic stem cells, as well as adult cell types that have proven amenable to rejuvenation and redifferentiation (Adv Drug Deliv Rev. 2014;69-70:254-69).
In one example of the quest for completely in vitro human-tissue designed valves, Dr. Jean Dubé of Laval University, Quebec, and his colleagues reported research on a human tissue–engineered trileaflet heart valve assembled in vitro using human fibroblasts. These cells self-assembled into living tissue sheets when cultured in the presence of sodium ascorbate. These sheets could be layered together to create a thick construct, with the ultimate goal of replacing the use of bovine pericardium tissue implants with ones made of autologous cells from the patient (Acta Biomater. 2014 Aug;10[8]:3563-70).
Currently, however, many of the preclinical studies of fully tissue engineered heart valves have shown retraction of the heart valve leaflets as a major mechanism of functional failure. This retraction is caused by both passive and active cell stress and passive matrix stress, according to a review by Inge A.E.W. van Loosdregt, Ph.D., and her colleagues at the Eindhoven (the Netherlands) University of Technology (J Biomech. 2014 Jun 27;47[9]:2064-9).
While all of these developmental issues regarding the use of fully tissue-engineered valves are being worked out, early clinical applications are already being found for a new generation of valve prostheses that take an intermediate approach, one that uses an implanted scaffolding material that allows autologous cell infiltration and replacement in vivo.
Two of the most prominent examples of these scaffoldings currently in investigation and in early clinical use for heart valve repair or replacement are the bovine pericardium-derived CardioCel (Admedus, Brisbane, Australia) and the porcine intestinal submucosa-derived CorMatrix ECM(CorMatrix Cardiovascular, Roswell, Ga.). CorMatrix ECM was approved by the Food and Drug Administration in 2005 for pericardial repair and reconstruction, and in 2007 for cardiac tissue repair. The FDA approved CardioCel in 2014 for use in the United States in pericardial closure and for the repair of cardiac and vascular defects in both adults and children.
Both technologies rely on the concept of matrix infiltration by autologous cells after implantation in order to create a living mimic of the patient’s own tissues.
CardioCel is a highly treated, bovine pericardium-derived, decellularized collagen matrix. It showed significant resistance to calcification in mitral and pulmonary implants in a juvenile sheep model as reported by Dr. Christian P. Brizard at Royal Children’s Hospital, Melbourne, and his colleagues (J Thorac Cardiovasc Surg. 2014 Dec;148[6]:3194-201). These investigators replaced the posterior leaflet of the mitral valve and one of the pulmonary valve cusps with patches in 10-month-old ewes. They compared the use of CardioCel in six ewes to a control group of four ewes repaired with autologous pericardium that was treated intraoperatively with glutaraldehyde, which is the standard default used at their institution for more than 2 decades as the best material for valve repair in their pediatric patients.
The primary end points of the study were thickening and calcium content. They found that all animals survived with normal valve echocardiography until sacrifice at 7 months. They reported that the bovine pericardium patches allowed accurate valve repair at both systemic and pulmonary pressure with preserved mechanical properties and more-controlled healing and without calcification as compared with the controls. (Calcification is a known major risk factor for the eventual failure of bioprosthetic valves.) Additionally, the bovine pericardium patched valves showed the in vivo development of dense but thin cellularized outer layers of mature collagen I, compared with the controls, which had outer layers that were much less dense and showed the presence of immature collagen III.
In another case of valvular use of the CardioCel material, at the recent American Association for Thoracic Surgery Mitral Conclave 2015, M. Bonnie Ghosh-Dastidar, Ph.D., and her colleagues from the Royal Brompton Hospital, London, reported on a severely ill patient with significant mitral regurgitation and an infected mitral valve with large vegetations on the anterior leaflets. The infected tissue was resected and a large patch of CardioCel bovine pericardium was used to reconstruct the leaflets. Postoperative assessment showed a competent mitral valve with good area of leaflet coaptation, according to Dr. Ghosh-Dastidar.
In his invited commentary on the animal-model research by Dr. Brizard, Dr. Niv Ad, director of cardiac surgery research at Inova Heart and Vascular Institute, Falls Church, Va., said that despite the promise of the CardioCel patches, there were a number of alternative approaches being investigated. “Other engineered materials currently being study include processes such as lyophilization, which has shown promising results in reducing inflammation. Another proposed approach is the use of decellularized vessels and patches with the promise of normal remodeling and growth, such as extracellular matrix and its potential for tissue regeneration.”
Dr. Ad also stated that, “the key bioengineering challenge is to determine how biologic, structural, and mechanical factors interact and function in vivo. The understanding of these factors will prove critical to the development of a clinically viable tissue-engineered heart valve,” (J Thorac Cardiovasc Surg. 2014 Dec;148[6]:3202-3).
An example of the use of extracellular matrix material referred to by Dr. Ad is the CorMatrix ECM, which is an extracellular matrix material derived from porcine small-intestinal submucosa, processed and decellularized.
Dr. Marc W. Gerdisch and his colleagues from the Franciscan St. Francis Heart Center, Indianapolis, reported on the results of treating 19 patients with mitral valve disease using the CorMatrix patch material for partial or subtotal leaflet repair or extension. There were three deaths unrelated to the repair and no instances of perioperative or late stroke. Two patients with a history of cancer and cancer therapy experienced failure of the initial repair, requiring reintervention. However, the other mitral valve repair patients continued to show good valvular function and no calcification on echocardiographic follow-up of 4 days to 48 months (Thorac Cardiovasc Surg. 2014 Oct;148[4]:1370-8).
And in 2015, CorMatrix Cardiovascular announced FDA approval of an investigational device exemption for an early feasibility study of their CorMatrix ECM Tricuspid Heart Valve in up to 15 patients at 5 U.S. centers (NCT02397668). Indications are for the surgical management of tricuspid valve disease not amenable to annuloplasty or repair, including tricuspid valve disease secondary to congenital heart disease in pediatric patients and adult endocarditis patients. The CorMatrix ECM Tricuspid Valve is a flexible, unstented valve acting as a 3‐D scaffold designed to function immediately as a prosthetic, but one constructed to permit native cellular infiltration and remodeling.
Ultimately, both the CardioCel and the CorMatrix materials are just the tip of an iceberg of research into tissue engineering as a clinical tool. And success and the wider adoption of any current or developing technologies will require the results of far-more-extensive studies and long-term clinical results.
At some future date, engineered total organ substitutes or the routine injection of genetically engineered stem cells may provide a practical alternative for treating a diseased or damaged heart. But for now, the most-likely scenario is the continued exploration of tissue engineering to develop the most durable, growth-, stress-, and biologically compatible patches, valves, and vasculatures possible – defined tools that can be adapted to current surgical techniques, designed to obtain the best repair of congenital or acquired heart disease conditions.
As with any transformative technology in medicine, the path from laboratory success and optimistic short-term clinical results to durable, long-term postoperative benefits may be a rocky one. But given the current enthusiasm, it certainly looks as if it will be a well-traveled road.
Dr. Brizard reported consulting and lecturing fees from Admedus. His research was supported with the assistance of a grant from Admedus. Dr. Gerdisch reported consulting fees and equity ownership in CorMatrix Cardiovascular.
Bioengineered tissues are showing promise in the treatment of valvular heart disease, according to the results of several early clinical and preclinical studies demonstrating the benefits of using heterologous substrates as scaffolding capable of promoting in vivo cell infiltration and remodeling.
Ultimately, cardiac tissue engineering seeks to develop the ideal material for replacement and repair of a variety of heart components – a material able to integrate, function, and, when necessary, grow and develop in a manner undifferentiated from normal cellular structures.
One of the most important areas of focus for such efforts is the development of heart valves and valve patches suitable for use in replacement or repair. The need is obvious: “The fact that literature continues to be published debating the best type of valve prosthesis is proof that, to date, the ideal valve substitute has not been found,” according to Cristian Rosu, Ph.D. and Dr. Edward G. Soltesz of the Cleveland Clinic (Semin Thorac Cardiovasc Surg. 2015 June 30 [doi: 10.1053/j.semtcvs.2015.06.007]).
Dr. Roşu and Dr. Soltesz go on to say that this lack of an ideal prosthetic heart valve leaves surgeons and their patients with a difficult choice at the time of valve surgery. The focus of their concern relates to how current bioprostheses are being used in younger and younger patients, and how these devices have a finite lifespan – requiring eventual reoperation and replacement, perhaps multiple times. In addition, calcification is a prominent and well-known risk of bioprosthetic valves, especially in children (Circulation. 2014 Jul 1;130[1]:51-60).
As for mechanical valves, although durable, they require a lifetime of anticoagulation therapy to prevent thrombosis. And the lack of growth potential found in both mechanical and current bioprosthetic devices is obviously a bane to pediatric valve therapy.
The latest efforts in tissue engineering therefore seek to develop valves and valve components that may be more permanent solutions by better mimicking natural valves.
But better mimicking of a natural valve is not an easy task, when such valves exist in “a near-perfect correlation of structure and function, enabling the valve to avoid excess stress on the cusps while simultaneously withstanding the wear and tear of 40-million repetitive deformations per year, equivalent to some 3 billion over a 75-year lifetime.” (“Principles of Tissue Engineering,” 4th ed. [London: Academic Press 2014, p. 813]).
The “holy grail” of tissue engineering, therefore, is to provide a completely in vitro–developed, autologous, fully cellularized, functional scaffolding for implantation that can live up to these requirements. In order to do this, extensive research into the search for the best cell sources and growth matrices and methods is underway, as illustrated by several recent reviews (Front Cell Dev Biol. 30 June 2015 [doi.org/10.3389/fcell.2015.00039] and Mater Sci Eng C. 2015 March 1;48:556-65).
Candidate cell types include a variety of embryonic stem cells, as well as adult cell types that have proven amenable to rejuvenation and redifferentiation (Adv Drug Deliv Rev. 2014;69-70:254-69).
In one example of the quest for completely in vitro human-tissue designed valves, Dr. Jean Dubé of Laval University, Quebec, and his colleagues reported research on a human tissue–engineered trileaflet heart valve assembled in vitro using human fibroblasts. These cells self-assembled into living tissue sheets when cultured in the presence of sodium ascorbate. These sheets could be layered together to create a thick construct, with the ultimate goal of replacing the use of bovine pericardium tissue implants with ones made of autologous cells from the patient (Acta Biomater. 2014 Aug;10[8]:3563-70).
Currently, however, many of the preclinical studies of fully tissue engineered heart valves have shown retraction of the heart valve leaflets as a major mechanism of functional failure. This retraction is caused by both passive and active cell stress and passive matrix stress, according to a review by Inge A.E.W. van Loosdregt, Ph.D., and her colleagues at the Eindhoven (the Netherlands) University of Technology (J Biomech. 2014 Jun 27;47[9]:2064-9).
While all of these developmental issues regarding the use of fully tissue-engineered valves are being worked out, early clinical applications are already being found for a new generation of valve prostheses that take an intermediate approach, one that uses an implanted scaffolding material that allows autologous cell infiltration and replacement in vivo.
Two of the most prominent examples of these scaffoldings currently in investigation and in early clinical use for heart valve repair or replacement are the bovine pericardium-derived CardioCel (Admedus, Brisbane, Australia) and the porcine intestinal submucosa-derived CorMatrix ECM(CorMatrix Cardiovascular, Roswell, Ga.). CorMatrix ECM was approved by the Food and Drug Administration in 2005 for pericardial repair and reconstruction, and in 2007 for cardiac tissue repair. The FDA approved CardioCel in 2014 for use in the United States in pericardial closure and for the repair of cardiac and vascular defects in both adults and children.
Both technologies rely on the concept of matrix infiltration by autologous cells after implantation in order to create a living mimic of the patient’s own tissues.
CardioCel is a highly treated, bovine pericardium-derived, decellularized collagen matrix. It showed significant resistance to calcification in mitral and pulmonary implants in a juvenile sheep model as reported by Dr. Christian P. Brizard at Royal Children’s Hospital, Melbourne, and his colleagues (J Thorac Cardiovasc Surg. 2014 Dec;148[6]:3194-201). These investigators replaced the posterior leaflet of the mitral valve and one of the pulmonary valve cusps with patches in 10-month-old ewes. They compared the use of CardioCel in six ewes to a control group of four ewes repaired with autologous pericardium that was treated intraoperatively with glutaraldehyde, which is the standard default used at their institution for more than 2 decades as the best material for valve repair in their pediatric patients.
The primary end points of the study were thickening and calcium content. They found that all animals survived with normal valve echocardiography until sacrifice at 7 months. They reported that the bovine pericardium patches allowed accurate valve repair at both systemic and pulmonary pressure with preserved mechanical properties and more-controlled healing and without calcification as compared with the controls. (Calcification is a known major risk factor for the eventual failure of bioprosthetic valves.) Additionally, the bovine pericardium patched valves showed the in vivo development of dense but thin cellularized outer layers of mature collagen I, compared with the controls, which had outer layers that were much less dense and showed the presence of immature collagen III.
In another case of valvular use of the CardioCel material, at the recent American Association for Thoracic Surgery Mitral Conclave 2015, M. Bonnie Ghosh-Dastidar, Ph.D., and her colleagues from the Royal Brompton Hospital, London, reported on a severely ill patient with significant mitral regurgitation and an infected mitral valve with large vegetations on the anterior leaflets. The infected tissue was resected and a large patch of CardioCel bovine pericardium was used to reconstruct the leaflets. Postoperative assessment showed a competent mitral valve with good area of leaflet coaptation, according to Dr. Ghosh-Dastidar.
In his invited commentary on the animal-model research by Dr. Brizard, Dr. Niv Ad, director of cardiac surgery research at Inova Heart and Vascular Institute, Falls Church, Va., said that despite the promise of the CardioCel patches, there were a number of alternative approaches being investigated. “Other engineered materials currently being study include processes such as lyophilization, which has shown promising results in reducing inflammation. Another proposed approach is the use of decellularized vessels and patches with the promise of normal remodeling and growth, such as extracellular matrix and its potential for tissue regeneration.”
Dr. Ad also stated that, “the key bioengineering challenge is to determine how biologic, structural, and mechanical factors interact and function in vivo. The understanding of these factors will prove critical to the development of a clinically viable tissue-engineered heart valve,” (J Thorac Cardiovasc Surg. 2014 Dec;148[6]:3202-3).
An example of the use of extracellular matrix material referred to by Dr. Ad is the CorMatrix ECM, which is an extracellular matrix material derived from porcine small-intestinal submucosa, processed and decellularized.
Dr. Marc W. Gerdisch and his colleagues from the Franciscan St. Francis Heart Center, Indianapolis, reported on the results of treating 19 patients with mitral valve disease using the CorMatrix patch material for partial or subtotal leaflet repair or extension. There were three deaths unrelated to the repair and no instances of perioperative or late stroke. Two patients with a history of cancer and cancer therapy experienced failure of the initial repair, requiring reintervention. However, the other mitral valve repair patients continued to show good valvular function and no calcification on echocardiographic follow-up of 4 days to 48 months (Thorac Cardiovasc Surg. 2014 Oct;148[4]:1370-8).
And in 2015, CorMatrix Cardiovascular announced FDA approval of an investigational device exemption for an early feasibility study of their CorMatrix ECM Tricuspid Heart Valve in up to 15 patients at 5 U.S. centers (NCT02397668). Indications are for the surgical management of tricuspid valve disease not amenable to annuloplasty or repair, including tricuspid valve disease secondary to congenital heart disease in pediatric patients and adult endocarditis patients. The CorMatrix ECM Tricuspid Valve is a flexible, unstented valve acting as a 3‐D scaffold designed to function immediately as a prosthetic, but one constructed to permit native cellular infiltration and remodeling.
Ultimately, both the CardioCel and the CorMatrix materials are just the tip of an iceberg of research into tissue engineering as a clinical tool. And success and the wider adoption of any current or developing technologies will require the results of far-more-extensive studies and long-term clinical results.
At some future date, engineered total organ substitutes or the routine injection of genetically engineered stem cells may provide a practical alternative for treating a diseased or damaged heart. But for now, the most-likely scenario is the continued exploration of tissue engineering to develop the most durable, growth-, stress-, and biologically compatible patches, valves, and vasculatures possible – defined tools that can be adapted to current surgical techniques, designed to obtain the best repair of congenital or acquired heart disease conditions.
As with any transformative technology in medicine, the path from laboratory success and optimistic short-term clinical results to durable, long-term postoperative benefits may be a rocky one. But given the current enthusiasm, it certainly looks as if it will be a well-traveled road.
Dr. Brizard reported consulting and lecturing fees from Admedus. His research was supported with the assistance of a grant from Admedus. Dr. Gerdisch reported consulting fees and equity ownership in CorMatrix Cardiovascular.
