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From valvular xenograft to valvular bioprosthesis: 1965–1970
From Valvular Xenograft to Valvular Bioprosthesis: 1965-1970 Alain Carpentier, MD, PhD Service de Chirurgie Cardio-vasculaire, HBpital Broussais, Paris, France
T
he research that led from the xenograft valve to the concept of the bioprosthesis is an example of the growing dependence of surgery on certain basic sciences. This presents the surgeon with two alternatives: either to learn the language of these sciences or to be relegated to the position of a manual worker. The first successful xenograft valve implantation in humans was carried out in September 1965 by Jean-Paul Binet, Jean Langlois, and myself. Being responsible for the valve preparation [l],I chose a mercurial solution with which I had experimented 2 years earlier with Robert Judet, the inventor of the artificial hip; we used this solution to preserve homologous skin for reconstruction of joints and noticed very little inflammatory reaction, although skin was known to be extremely antigenic. Contrary to experimental findings and despite early good clinical results, the xenograft valves preserved in this mercurial solution tended to deteriorate after 6 months. This early experience showed that the most important factor affecting valve durability was the method of preparation, and that the dream of graft regeneration by creeping substitution of host fibroblasts failed to materialize. The cellular ingrowth that did occur proved harmful, as the cells invading the graft tissue were most often inflammatory in nature. It became obvious that to prolong the durability of these valves it would be necessary to prevent cellular penetration. This aim was the subject of my research during the years 1966 and 1967, a research oriented in two directions: chemical treatment and mechanical protection.
Chemical Treatment: The Way to Glutaraldehyde Preservation Because the inflammatory reaction observed in explanted xenografts involved mainly immunologically competent cells leading to collagen denaturation, I tried to find a chemical treatment capable of decreasing the antigenicity of the tissue and increasing its physicochemical stability. However, this was far beyond my capability in and knowledge of chemistry, and I found it necessary to go back to the university to obtain a PhD in biochemistry. I was 33 years old, 10 years older than the other students from whom I hid my true position as assistant professor of surgery so as not to compromise the reputation of cardiac Presented at the World Congress on Heart Valve Replacement, San Diego, CA, Jan 1.518, 1989. Address reprint requests to Dr Carpentier, Service de Chirurgie Cardiovasculaire, HSpital Broussais, 96, rue Didot, 75674 Paris, France.
0 1989 by The Society of Thoracic Surgeons
surgery by the rather poor grades I got on the various examinations! I worked on cross-linking inducing factors either to introduce cross-linkages into the tissue (acrolein, succinyldehyde, glyoxal, glutaraldehyde, formaldehyde, dialdehyde starch) or to reinforce cross-linkages (sodium borohydride). Among the many substances tested, glutaraldehyde, a product widely used in electron microscopy, appeared to be the most effective for decreasing the antigenicity and increasing the stability of the tissue as shown by subcutaneous implantation of treated tissue in the rat and by numerous physical or immunological tests. Based on these experiments, often forgotten today, glutaraldehyde was adopted as the method of choice in heterologous tissue preservation. My colleagues and I published our findings in 1969 [2].
Mechanical Protection: The Concept of Greffe Protkgke Because experimental and clinical data showed that inflammatory cellular penetration occurred chiefly at the graft-host interface, a physical barrier, ie, a thin cloth or a stent, was interposed between the host and the valve, and the aortic sleeve was covered with the same material (Fig 1).This concept of the greffe protigke and its combination with the first frame-mounted valve were introduced in 1966 and 1967, respectively [3, 4). Various techniques were proposed over the years to solve the peculiar problems raised by the attachment of the muscular septum to the right coronary cusp in animals (Fig 2). As a result of glutaraldehyde treatment and mechanical protection against cellular penetration, the valve is no longer a graft in the strict sense but a prosthesis. I coined the term bioprosthesis to recall its biological origin and its prosthetic fate [5]. The bioprosthesis falls somewhere between a graft and a synthetic prosthesis, and it is hoped that it incorporates the advantages of both. In contrast to the graft, the durability of the bioprosthetic valve becomes dependent on the stability and the inertness of the biological material and not on regeneration by host cells. With Charles Dubost, my colleagues and I implanted the first bioprosthesis in March 1968 (Fig 3) [2]. The patient survived for 18 years with his original valve. Aware of the development of bioprosthetic valves, Albert Starr advised Edwards Laboratories to enter the field of tissue valves, and because of his recommendation, I was invited to Santa Ana in 1969 to present my work. I accepted the proposal of Will Perie, President of Edwards Laboratories, that I advise them in the development of a valvular bioprosthesis on the condition that the valve not Ann Thorac Surg 1989;48:S734
0003-4975/89/$3.50
574
CARPENTIER VALVULAR XENOGRAFT T O BIOPROSTHESIS
Cellular in-growth
'Protec!ed groft
A n n Thorac Surg 1989;48:S734
Frome -mounted protected groft
A B C Fig I . The concept of greffe protegee: (A) penetration of host cells into graft (1965); (B)greffe protigie (1966); and (C) greffe protbgie mounted on a stent (1967).
be released on the market for a minimum of 4 years after implantation. Warren Hancock was vice-president of Edwards Laboratories at the time, and he was present at this meeting. Some months later, he left Edwards Laboratories, thus freeing himself from my requirements. Without any restrictions, he developed the Hancock valve, which became commercially available in 1970. Hancock Laboratories made a tremendous contribution as far as mass production and popularization of valvular bioprostheses were concerned, a little too much popularization in my opinion, as very few people at that time listened to my words of caution in regard to the long-term fate of these valves, particularly in children. This previously unpublished story is interesting mainly because it points out the foresight of Albert Starr, who must be credited, among his other contributions, for having introduced valvular bioprostheses to the United States without regard to the effect on his own valve. Much of the remainder of the story, ie, the development of bioprosthetic valves, whether porcine valves or bovine pericardium, whether high profile or low profile, whether yellow or blue, is known, but not its ending. Twenty
Docrdn-cwered right coronary
Incorporated right coronary
,
\
!
1 I I
I
II
, .-__-/ Carpentier, 1966
A
lonescu and colleagues. 1967
B
Carpentler. 1967
C
Fig 2 . Stents were introduced in 1966 before glutaraldehyde preservation. Several techniques were used to reinforce the right coronary cusp (B,C), which was made fragile by trimming ( A ) .
Fig 3. First glutaraldehyde-preserved,frame-mounted porcine valve implanted in a human. Note that the aortic sheath and the struts were not covered with fabric in this early model.
years later, we know that the aim has been only partially achieved. Although low thrombogenicity has been confirmed, an acceptable stability has been observed only in patients older than 35 years. We know that the older the patient, the longer the valve durability. Calcification of the tissue remains a stumbling block in younger patients. The current efforts of my wife, Sophie, who has helped me since 1974, and myself are directed toward the development of chemical methods of calcium mitigation so that, one day, children will have the benefit of a durable, nonthrombogenic valvular prosthesis.
References 1. Carpentier A. Utilisation dheterogreffes dans le traitement des lesions de I'appareil valvulaire aortique. Etude biologique et technique. Premiers resultats cliniques. [These Med.]. Pans, France, 1966. 2. Carpentier A, Lemaigre G, Robert L, Carpentier S, Dubost C. Biological factors affecting long-term results of valvular heterografts. J Thorac Cardiovasc Surg 1969;58:467-81. 3. Carpentier A, Chanard J, Briotet JM, Laurent D, Dubost C. Remplacement de I'appareil valvulaire mitral par des heterogreffes heterotopiques armees. Presse Med 1966;75:160.3-6. 4. Carpentier A, Blondeau P, Laurens P, Hay A, Laurent D, Dubost C. Mitral and tricuspid valve replacement with framemounted aortic heterografts. J Thorac Cardiovasc Surg 1968; 56:3. 5. Carpentier A. The concept of bioprostheses. A new approach in the treatment of valvular diseases. Cardiovasc Res 1970100.
T
he research that led from the xenograft valve to the concept of the bioprosthesis is an example of the growing dependence of surgery on certain basic sciences. This presents the surgeon with two alternatives: either to learn the language of these sciences or to be relegated to the position of a manual worker. The first successful xenograft valve implantation in humans was carried out in September 1965 by Jean-Paul Binet, Jean Langlois, and myself. Being responsible for the valve preparation [l],I chose a mercurial solution with which I had experimented 2 years earlier with Robert Judet, the inventor of the artificial hip; we used this solution to preserve homologous skin for reconstruction of joints and noticed very little inflammatory reaction, although skin was known to be extremely antigenic. Contrary to experimental findings and despite early good clinical results, the xenograft valves preserved in this mercurial solution tended to deteriorate after 6 months. This early experience showed that the most important factor affecting valve durability was the method of preparation, and that the dream of graft regeneration by creeping substitution of host fibroblasts failed to materialize. The cellular ingrowth that did occur proved harmful, as the cells invading the graft tissue were most often inflammatory in nature. It became obvious that to prolong the durability of these valves it would be necessary to prevent cellular penetration. This aim was the subject of my research during the years 1966 and 1967, a research oriented in two directions: chemical treatment and mechanical protection.
Chemical Treatment: The Way to Glutaraldehyde Preservation Because the inflammatory reaction observed in explanted xenografts involved mainly immunologically competent cells leading to collagen denaturation, I tried to find a chemical treatment capable of decreasing the antigenicity of the tissue and increasing its physicochemical stability. However, this was far beyond my capability in and knowledge of chemistry, and I found it necessary to go back to the university to obtain a PhD in biochemistry. I was 33 years old, 10 years older than the other students from whom I hid my true position as assistant professor of surgery so as not to compromise the reputation of cardiac Presented at the World Congress on Heart Valve Replacement, San Diego, CA, Jan 1.518, 1989. Address reprint requests to Dr Carpentier, Service de Chirurgie Cardiovasculaire, HSpital Broussais, 96, rue Didot, 75674 Paris, France.
0 1989 by The Society of Thoracic Surgeons
surgery by the rather poor grades I got on the various examinations! I worked on cross-linking inducing factors either to introduce cross-linkages into the tissue (acrolein, succinyldehyde, glyoxal, glutaraldehyde, formaldehyde, dialdehyde starch) or to reinforce cross-linkages (sodium borohydride). Among the many substances tested, glutaraldehyde, a product widely used in electron microscopy, appeared to be the most effective for decreasing the antigenicity and increasing the stability of the tissue as shown by subcutaneous implantation of treated tissue in the rat and by numerous physical or immunological tests. Based on these experiments, often forgotten today, glutaraldehyde was adopted as the method of choice in heterologous tissue preservation. My colleagues and I published our findings in 1969 [2].
Mechanical Protection: The Concept of Greffe Protkgke Because experimental and clinical data showed that inflammatory cellular penetration occurred chiefly at the graft-host interface, a physical barrier, ie, a thin cloth or a stent, was interposed between the host and the valve, and the aortic sleeve was covered with the same material (Fig 1).This concept of the greffe protigke and its combination with the first frame-mounted valve were introduced in 1966 and 1967, respectively [3, 4). Various techniques were proposed over the years to solve the peculiar problems raised by the attachment of the muscular septum to the right coronary cusp in animals (Fig 2). As a result of glutaraldehyde treatment and mechanical protection against cellular penetration, the valve is no longer a graft in the strict sense but a prosthesis. I coined the term bioprosthesis to recall its biological origin and its prosthetic fate [5]. The bioprosthesis falls somewhere between a graft and a synthetic prosthesis, and it is hoped that it incorporates the advantages of both. In contrast to the graft, the durability of the bioprosthetic valve becomes dependent on the stability and the inertness of the biological material and not on regeneration by host cells. With Charles Dubost, my colleagues and I implanted the first bioprosthesis in March 1968 (Fig 3) [2]. The patient survived for 18 years with his original valve. Aware of the development of bioprosthetic valves, Albert Starr advised Edwards Laboratories to enter the field of tissue valves, and because of his recommendation, I was invited to Santa Ana in 1969 to present my work. I accepted the proposal of Will Perie, President of Edwards Laboratories, that I advise them in the development of a valvular bioprosthesis on the condition that the valve not Ann Thorac Surg 1989;48:S734
0003-4975/89/$3.50
574
CARPENTIER VALVULAR XENOGRAFT T O BIOPROSTHESIS
Cellular in-growth
'Protec!ed groft
A n n Thorac Surg 1989;48:S734
Frome -mounted protected groft
A B C Fig I . The concept of greffe protegee: (A) penetration of host cells into graft (1965); (B)greffe protigie (1966); and (C) greffe protbgie mounted on a stent (1967).
be released on the market for a minimum of 4 years after implantation. Warren Hancock was vice-president of Edwards Laboratories at the time, and he was present at this meeting. Some months later, he left Edwards Laboratories, thus freeing himself from my requirements. Without any restrictions, he developed the Hancock valve, which became commercially available in 1970. Hancock Laboratories made a tremendous contribution as far as mass production and popularization of valvular bioprostheses were concerned, a little too much popularization in my opinion, as very few people at that time listened to my words of caution in regard to the long-term fate of these valves, particularly in children. This previously unpublished story is interesting mainly because it points out the foresight of Albert Starr, who must be credited, among his other contributions, for having introduced valvular bioprostheses to the United States without regard to the effect on his own valve. Much of the remainder of the story, ie, the development of bioprosthetic valves, whether porcine valves or bovine pericardium, whether high profile or low profile, whether yellow or blue, is known, but not its ending. Twenty
Docrdn-cwered right coronary
Incorporated right coronary
,
\
!
1 I I
I
II
, .-__-/ Carpentier, 1966
A
lonescu and colleagues. 1967
B
Carpentler. 1967
C
Fig 2 . Stents were introduced in 1966 before glutaraldehyde preservation. Several techniques were used to reinforce the right coronary cusp (B,C), which was made fragile by trimming ( A ) .
Fig 3. First glutaraldehyde-preserved,frame-mounted porcine valve implanted in a human. Note that the aortic sheath and the struts were not covered with fabric in this early model.
years later, we know that the aim has been only partially achieved. Although low thrombogenicity has been confirmed, an acceptable stability has been observed only in patients older than 35 years. We know that the older the patient, the longer the valve durability. Calcification of the tissue remains a stumbling block in younger patients. The current efforts of my wife, Sophie, who has helped me since 1974, and myself are directed toward the development of chemical methods of calcium mitigation so that, one day, children will have the benefit of a durable, nonthrombogenic valvular prosthesis.
References 1. Carpentier A. Utilisation dheterogreffes dans le traitement des lesions de I'appareil valvulaire aortique. Etude biologique et technique. Premiers resultats cliniques. [These Med.]. Pans, France, 1966. 2. Carpentier A, Lemaigre G, Robert L, Carpentier S, Dubost C. Biological factors affecting long-term results of valvular heterografts. J Thorac Cardiovasc Surg 1969;58:467-81. 3. Carpentier A, Chanard J, Briotet JM, Laurent D, Dubost C. Remplacement de I'appareil valvulaire mitral par des heterogreffes heterotopiques armees. Presse Med 1966;75:160.3-6. 4. Carpentier A, Blondeau P, Laurens P, Hay A, Laurent D, Dubost C. Mitral and tricuspid valve replacement with framemounted aortic heterografts. J Thorac Cardiovasc Surg 1968; 56:3. 5. Carpentier A. The concept of bioprostheses. A new approach in the treatment of valvular diseases. Cardiovasc Res 1970100.