Implantable medical devices are introduced into the body to perform certain functions, either as a structural or functional replacement and are designed to function successfully without requiring immunosuppression. The term 'biomaterial' is not appropriate and to the ear, it may appear to refer to a biological origin, when most implantable devices are not. Rather when an implanted device is accepted by the system with minimal reaction, serves a function it was designed to in a lifetime, and is biologically compatible with the subject in whom implanted, it is termed a biologically acceptable implant or a biomaterial. The use of such materials, ordinarily foreign to the body, but able to carry out a function when the original and natural part is absent, is not new. Usually, a biodegradable and durable material that will ultimately be absorbed or replaced by the biological tissues leaving minimal or no trace at all will be preferable. The search and use of replacement materials best suited to the structural and functional requirements were there from very early times. Alexis Carrel initially hypothesized the future use of biomaterials. Voorhees extensively studied the properties and even suggested patch arthroplasty techniques. From the engineering perspective, designing implants for medical use has its challenges. The problem had to be understood, both the biological standpoint was important and why it was present in that position and its function. Dental surgery was an early example and the knowledge that inanimate structures were dealt with made a difference. The now commonly used term 'stent' is from Charles Stent. It is a scaffolding on which the new teeth are set. Trial and error were required to find out the best material needed for the constitution of such contraptions. Initially, attaining structural similarity was the goal. Later with the advancement of procedures and a better understanding of human anatomy, functional properties were also looked into. Charles Stent was involved in making an impression of defects after a loss of teeth; however, some authors claim that the origin of the word stent is associated with the Scottish word 'stynt' or 'stent', meaning stretched out river fishing nets. Whatever it is, the word 'stent' has become very common and is usually applied to the minimally invasive procedure of keeping the coronary vessels open after balloon angioplasty to keep the blocked or stenosed arteries open so that the distal tissues are normally perfused. From the very first day of cardiac and vascular surgery, the use of biologically compatible materials was relevant. Cardiac surgery is relatively new and from the very beginning, there were attempts to collaborate with the engineers to find a solution to replace the disorganized and dysfunctional structures essential for normal function. The big business houses like IBM, General Motors, Ford, the medical division of Fiat, etc., almost everybody pitched in. First, a device was built that for a short period could mimic the function of a heart and the lung. Then replacement designs for the cardiac valves were pursued. The great wars and war injuries provided the surgeon with the requisite experience and courage to venture. Physicians started to understand valvular pathologies and Charles Hufnagel was the first to implant a methyl methacrylate-housed ball-cage valve in the descending thoracic aorta. It was historic that Dwight Emory Harken did the first sub-coronary implantation on the 10th of March 1960. A day or couple later Nina Braunwald did an orthotopic mitral valve replacement with suture implantation of chordae. Remarkably both used design and materials unique to themselves and paved a pathway for future development.
Valves for human implantation -- Hufnagel, Harken, Nina Braunwald, and Starr-Edwards: the prototypes.
Simultaneous research was going on with other materials and a sincere effort was on to find the best possible method. The role of Dr Albert Starr and his engineer friend Myles Edward in popularizing the Starr-Edward ball cage 1260 and 6120 valves is legendary. These valves have ruled for a long time and the present preference is for a bileafllet design with polished graphite as the chosen material. In other prostheses, titanium became the favourite because it was strong and incited the least inflammatory reaction when implanted. Recent interest has been in increasing a hemodynamic flow profile and further improving the existing opening leaflet angle by changing the design of the butterfly grooves and leaflet hinge regions of the housing. Polished graphite has become the material of choice for the construction of these valves because of its low thrombogenicity. Though there has been an improvement and several agents have come on the market, an invasive P-time with INR is still a periodic requirement, and ingestion of a proper anticoagulant is a necessity. The recent guidelines suggest the addition of antiplatelet agents over and above. The use of biomaterials woven into cloths saw their use mainly in vascular surgery. Arterioplasty, bypass grafting, or replacement of diseased portions of large vessels required such cloths. An understanding of the pathophysiology of the defect is necessary before deciding on the nature of the material to be used. The choice of material was important too. It could be anything from metals, ceramics, or plastics, provided it was accepted by the biological tissue and incited a minimal reaction. The use of an implant as a prop mainly was required in orthopaedic surgery of old times. Newer and biodegradable over a certain time materials have been developed which has not only revolutionized the process but also instigated a neo-tissue formation reaction. It is estimated that a significant number of urban people with easy access to medical facilities are implanted with devices that help them to live long and qualitatively better. A variation between 5 to 10 % is normal and the bulk is made of pacemakers and similar devices. There are some attributes of a material to be biologically accepted for implantation and these are : 1. Corrosion free. 2. No leaching of material into the surrounding tissue. 3. Structurally conforming to original anatomy. 4. Functionally satisfactory and within the environment of the body. 5. No deformation or displacement. 6. The functional requirements and properties have to be at least comparable to autogenous tissue. 7. Durable - both medium and long term. 8. Resistant to infections and rejection. In addition, tests recommended and usually done nowadays before a market launch are: 1. Cytotoxicity. 2. Genotoxicity and mutability. 3. Carcinogenicity. 4. Reproductive toxicity. 5. Immunogenicity. 6. Irritability. Modern biomedical engineers also research the stress a material can withstand when subjected to various sterilization methods. Earlier a hit-and-run policy was adopted, and success was evaluated if minimal adverse effects were there following implantation. The story was the same for a skull covering, an orthopaedic implant, or pacemakers. The scene was slightly different for cardiac prostheses. There may be valves for replacement, cloths or sheets for the repair of defects and there may be conduits (dedicated or with valve-composite conduits). The pacemakers were the first implanted prostheses and allowed a better quality of later life. Pacing generators have undergone revolutionary changes. The circuit, a small computer, was boxed in a hermetically sealed unit and protected by epoxy then. Araldite was just developed by the then-pharmaceutical giant Ciba-Geigy and proved an excellent implantable material. This not only encased the circuit but also contained the then-available dual mercury zinc batteries. Aluminum was used as the final casing material. The whole unit was no bigger than a Kiwi shoe polish-can popular at that time. The coiled electrodes were the only structural components, connected to the generator and introduced endo-venous via a basilic vein.
Among the metals, titanium is finding favour owing to its lightweight and strength. Shape-memory alloys increasingly find use in minimally invasive trans-catheter valve implantations. Nickel-titanium alloy nitinol is a common example. Self-retaining and non-knot-requiring nitinol-based atraumatic sutures have been developed for coronary revascularization. However, the cost is very high and hence, it has not become popular. Ceramics find best use in dentistry and orthopaedic surgery (zirconium in hip arthroplasty). There has been a recent spurt in interest in MRIs and consequently, a reduction in ferromagnetic compounds is contemplated. MRI-conditioned devices for implantation in heart rate & rhythm-controlling devices have become a fashion. The use of zip locks for sternal apposition has of late become common and an all-carbon valve and avoidance of metals in prosthetic materials are helping the MRI cause. In today's world plastics are ubiquitous and they are favored because of their diverse forms, moldability, biological acceptability, easy availability, and strength. These are organic polymers meaning that there is a profusion of carbon atoms in the basic monomer around which the covalent bond of other elemental atoms is with the linkage of the monomers to form a large molecular structure. The use of plastics caught the imagination of the practicing physicians of that time and these in various forms were explored as implantable materials. Meshes, sheets, and cylindrical forms were initially experimented on. Whenever a foreign implanted material is used in the body, the principal concern of the physician is intravascular clot formation. Since its advent, no new material has been discovered that can compete with heparin. The oral anticoagulants of the coumarin group are mainly used for maintenance and the antiplatelet agents do not prevent the formation of clots in the circulation when foreign prosthetic material is present. Observational studies have shown that the presence of an endothelial lining is essential for the prevention of clot formation and neo-endothelialization, in situations where either a repair or interposition grafting has to be done and begins at the newly formed suture edges. It is a slow and gradual process, and it takes a considerable time if the breach or graft is large. Initially, a proteinaceous biofilm is formed providing some degree of protection which is gradually replaced by the endothelial cells. Polythene, and other petroleum derivatives, have been the most commonly used bio-implants till recent times. The acrylic acid derivative polymethyl methacrylate or PMMA was used in chest wall reconstructions earlier and still finds its place as reliable bone cement. In the early times, a thin layer of PMMA sheet was placed between two meshes and the whole thing was used to cover a chest-wall defect. Silicone was found better, and Silicone rubbers are preferred for the construction of biomedical tubing. This is proven to prevent an exponential rise of pressure whenever air is injected into endotracheal tube balloons made of silicone rubber. Apart from the use of gold as a dental replacement, titanium is favoured owing to its strength. However, though strong, malleability is a problem. It has very weak magnetic properties, not attracting any immunological reaction, and has a very lessened power of inviting local tissue reactions making it a popular choice as an implantable material for biologically relevant prostheses. The Japanese have of late developed titanium fibre-based implantable material which is more malleable and thus may solve the rigidity problem of titanium sheets Graphite is another strong structural material that has attracted much interest. The beauty of the material is that it can be a part of the all-carbon implantable valvular prostheses and at the same time, a nanotube can be made. Graphite is the least thrombogenic and was initially used to cap nuclear warheads. Later it was incorporated into implantable medical devices. However, as of now, only rigid structures can be considered and sewable cloths are not available. Nylon, Vinyon-m, Ivalon sponge, and a host of other materials have been used and tested as vascular conduits since early times. Additionally, these materials could be moulded exactly like the original structure. Patency was never a problem, and these materials were biocompatible. However, they did not stand up to the pulsatility standards, ability to withstand shear stress, durability, and other factors. Only molded Dacron and Teflon in the conduit form could match the characteristics of flowing blood to a reasonable extent and easy sutureability makes Dacron conduits the preferred choice. These remain materials of choice, and Teflon small diameter tubes have a patency advantage, almost approximately similar to that of autogenous venous conduits in the longer run.
There has been some pioneering work in the construction of conduits for the passage of blood and valves within the circulation from biodegradable matrices. Additional advancements have been observed in mimicking natural structures. Nets and meshes are easy to construct but when it comes to complex valve-like structures, the difficulty starts. To succeed in creating a successful bioengineered vascular prosthesis the following objectives should be met: (i). The engineered substance should have an extracellular matrix of sufficient quality to provide suitable tensile strength, suture retention, and non-reactive properties. A focus on the production of suitable amounts of high-quality cross-linked vascular collagen types I and III is probably necessary for any biologically engineered artery to be successful. (ii). To minimize risks of inflammation, foreign-body response, and immune recognition, the vascular tissue matrix should be of human origin and without substantial synthetic material additives or artificial covalent cross-linking. (iii). If the engineered artery is cellular, even if the cells are nonviable, those cells should be autologous to prevent immune recognition, degradation, and aneurysm formation in the implanted vessels. (iv). Once implanted, the engineered arteries should have the potential to be remodelled, repopulated, and rejuvenated by the host. (v). For small-calibre or low-flow arterial bypass applications, it is likely that a suitable non-thrombogenic luminal surface is required. This surface may be either cellular or biochemical, but it should prevent blood coagulation contact activation, platelet adhesion and activation, and thrombosis in the arterial system.
This is a magnified view of a portion of knitted Dacron graft for vascular interposition. Similar patches are also sutured to repair tissue loss or defects. There crimping of the cylindrical vascular prosthesis allows versatility in placement and stretchability when the length is considered. To this velour, filaments are added which allows better anchoring, and together with the porous nature of such materials neo-endothelialization of the inner surface proceeds faster and efficiently.
There is a raging debate on the use of knitted and woven fabric with pores as biomaterials. It should be realized that the knitted fabric is more stretchable than a same-sized woven one and space-occupying, the cumbersome loom is required for weaving fabrics, whereas only two sticks with needle points suffice for a knitted material. Again porosity, a measure of the tightness of the fabric, allows better tissue ingrowth. Thus, both anchoring to the native area and neo-endothelial formation and encroachment are satisfactory. There was a comparison by Robicsek with a fabricated bifurcated vascular Dacron prosthesis where one limb of the bifurcation was made of a knitted material while the other limb was constructed from the woven fabric. However, no statistically significant difference between the two was found after a long follow-up. Needle pass when compared is found to be better with the knitted fabric. This tilts the opinion in favour of a knitted bioprosthetic graft.
Complete neo-endothelialization of a cylindrical vascular interposed conduit is always preferred. There is evidence from animal models that the process starts at the anastomotic and it is a long-drawn-out affair. Complete endothelial covering never happens, and studies are not conclusive about the effect of external agents and seeding of cells (even stem cells) on the process. Leakage of blood from the graft surface can be troublesome and often fatal. Various methods like prior clotting, with or without autoclaving, were advocated. However, these methods toughened the internal surface further. The present preference is for a collagen coating or an albumin painting of the outer surface. This effectively stops the leakage and gives time for the collagen or albumin to be absorbed into the body. Controlled systemic anti-coagulation takes care of any chance of formation of clots and a smooth vascular passage is ensured.
Dacron polyethene terephthalate, (PET) and Teflon (polytetrafluoroethylene, PTFE) are the preferred plastics when vascular conduits are constructed. Dacron and Teflon are the brand names of a family of petroleum-derived plastics. Both can be produced as sheets, shaped tubes, or other desired forms. As vascular conduits, both are reliably provided an anti-coagulant is used. Reasonable patency, though inferior to autogenous material like the vein, over time ensures use in a variety of situations. The cloth material of Dacron is favored again for the ease of sutureability and double velour filaments are added to promote fibrosis and neo-endothelialization. Both weaved or knitted forms are available, but the porous woven form with additional double velour for the promotion of fibrotic binding with surrounding tissue is preferred. Teflon is tough to suture, and the suture holes take time to stop troublesome bleeding as they tend to cut. Extended polytetrafluoroethylene (e-PTFE) conduits have been developed with intervening nodes and internodes to overcome this problem. Composite valved conduits with dilatations for sinuses have been created for complex root replacement procedures from Dacron. Dacron conduits are preferred additionally because they are breathable and will permit some diffusion of fluids across the wall. The story of Sparks-mandrel grafts where gradually tapered conduits were evaluated and not found satisfactory to patency is still fresh. Below-knee revascularization remains taboo. Infinite possibilities are possible, and the following picture is evidence where multiple Dacron grafts are used to their potential by one of our colleagues -------
A few words about the changing treatment methods of major blood vessel diseases. Nowadays the need for exposure and morbid dissections can be avoided. Less invasive vascular access followed by the introduction of a stented and walled graft is done. The pathological area is covered and only a landing area is needed. The prosthesis is pre-measured radiologically and here also Dacron is preferred due to its better handling properties. Branched grafts to cover large vessels when junctional areas are involved are available now. This has reduced the morbidity and mortality in selected aneurysms and dissections to a large extent.
Most of these procedures are a combination of surgical exposure followed by endovascular catheter manipulation and placement of a catheter-delivered covered stent with subsequent dilatation to keep it in position. Scaffolding with shape-memory alloy is usually done.
It was ironic that Gruentzig was allowed a poster presentation only for the angioplasty procedure based on which Uhlrich Sigwart advanced the intra-coronary stenting with a non-collapsible scaffolding. The materials used for intra-vascular stenting have improved and even drug-eluting stents are on the market. This not only revolutionized revascularization to distal parts but has saved numerous cardiac patients who would have otherwise died or become crippled due to myocardial infarction.
The procedure changed coronary revascularization, so much so that non-inferiority trials were designed, and PCI was considered an alternative to surgical revascularization in many situations.
Ingenuity and smart geometric designs have improved many implanted prostheses, especially bio-prosthetic valves. The chosen substance still varies, and the best material is selected for a particular reason. This is an evolving subject and with modern experimental and research techniques, the possibilities are limitless.
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