Biomimetics - Biologically Inspired Technologies - Yoseph Bar Cohen Episode 2 Part 7 pps

the recent years, and implants with textured surfaces have been developed in an effort to allow bone to grow into the implant, this theoretically has the advantage of allowing much stronger biological cementing. One of the long-term problems after hip replacement is loosening of the components, which can result in bone loss and pain. This restricts the use of total hip replacement among younger patients. This happens due to very small plastic particles produced by the wearing of the cup. Recently metal on metal joints have regained popularity and are particularly suited for the hip joint replacement in middle age patients since it gives a much longer lasting results compared to the other hip replacements (Dorr et al., 2000). Parallel developments allowed the development of total knee replacement. Initial attempts were to replace the joint cavity with hinges which can cover the joint space to reduce friction. But problems with loosening and infection frequently occurred. Frank Gunston developed a metal on plastic knee replacement joint in 1968 (Gunston, 1971). A three component knee-joint prosthesis was proposed by John Insall in 1972 which covered the femur, tibia, and the patella, and were held in place using cement (Ranawat et al., 1975). This has resulted in the development of the modern knee-joint prosthesis. Currently more than 150,000 knee-joint replacements are undertaken in United States alone (Noble et al., 2005). Similar to the hip prosthesis, attempts have been underway in recent years to achieve a cementless joint replacement, using biological ability to glue these components together by allowing new bone growth in the roughened surfaces of these devices, which then can give strength and eliminate the need for artificial gluing materials that could come loose. 18.10 BIO-ARTIFICIAL PANCREAS Long standing diabetes mellitus (types I and II) results due to the inability of the pancreas to secrete insulin. Therapy has been focused at administering the insulin exogenously to achieve acceptable blood sugar levels, however, it is often difficult to manage. Transplantation of the isolated islet cells (which secrete insulin) although promising is limited due to the associated need for immunosup- pression and limited organ supply. Devices such as microencapsulated islets (small diameter spherical chamber), and microencap- sulated islets (including hollow fiber, disk-shaped diffusion chambers and Millipore cellulose membranes) have been proposed (Lanza et al., 1992; Lim and Sun, 1980; Reach et al., 1981; Sullivan et al., 1991). Advancements in glucose sensing and insulin sensing technology have allowed developing automated closed loop insulin delivery systems that can deliver insulin in a more physiologic way. One such system currently undergoing clinical trials is a diffusion chamber for a bio-artificial endocrine pancreas (Bio-AEP), which is constructed by placing pancreatic islet cells, trapped in a scaffold; this is sandwiched between semipermeable membranes, and shielded by silicone (Hirotani et al., 1999). Although some of the results achieved in animal studies have been difficult to reproduce in large animal models, this therapy holds promise for the future treatment of diabetes mellitus. 18.11 VISUAL PROSTHESIS (ARTIFICIAL EYE) The understanding of the mammalian visual system has given impetus for conceptualizing an artificial visual prosthesis that can be used in the profoundly blind. The goal of these systems is to produce a visual perception to allow activities like reading, recognizing shapes and faces, negoti- ating complex spaces, and giving the perception of light surroundings. This is dealt with in greater detail in Chapters 11 and 17. Bar-Cohen : Biomimetics: Biologically Inspired Technologies DK3163_c018 Final Proof page 462 21.9.2005 3:40am 462 Biomimetics: Biologically Inspired Technologies 18.12 ARTIFICIAL SKIN SUBSTITUTES Successful application of skin substitutes has been applied widely in the clinical field for a few decades now. The development of skin substitutes or artificial skin began with growing sheets of cells in culture media and has progressed to developing complex structures with bi-layered skin that mimics the human skin. A deeper dermal element is constructed using synthetic epidermis. Currently there are three approaches used for manufacturing artificial skin, the gel approach where cells are grown in a gel of extracellular material like collagen; the scaffold approach where porous scaffolds created from collagen or synthetic material are used to allow cells to be seeded subse- quently (Jones et al., 2002); the third approach entails, self-assembly, it is still in animal testing stage and has to await clinical application. Some of the artificial skin substitutes available are, Alloderm 1 introduced in market in 1992 and is based on treating fresh cadaver skin in which the epidermal layer is removed and cellular components are destroyed (Bello et al., 2001). The freeze drying of this skin substitute renders it immunologically inert and hence is not rejected by the recipient (Losee et al., 2005; Terino, 2001). Integray approved in 1996 by FDA is another skin substitute available commercially and is made from cellular collagen and glycosaminoglycans matrix (Winfrey et al., 1999). The dermal compon- ent is made of collagen and the epidermal element is substituted by synthetic silicon. Dermagraft 1 is an allogenic dermal substitute, it comprises of a scaffold of polyglactin seeded with allogenic fibroblasts (Eaglstein, 1998). This is now used to treat skin ulcers and burn wounds. Another allogenic frozen dermal substitute is TransCyte 1 , which is used as a temporary replacement for wounds and burns (Noordenbos et al., 1999). It is created by seeding fibroblasts into a scaffold made from nylon mesh and silicone sheet. Bilayered substitutes are composed of allogenic keratinocytes seeded on a nonporous collagen gel and covered with a bovine collagen scaffold containing fibroblasts (OrCel 1 ). They offer the more biologically mimicking skin substitute (Still et al., 2003). 18.13 ARTIFICIAL BLOOD Inadequate oxygen delivery to the tissues is common sequelae when significant blood loss occurs due to trauma or surgery. This is commonly treated in clinical practice by administering donated human blood. However, the availability of donors and the risk of transmission of infections limit this approach. Fatal reactions can occur due to a mismatch or presence of antibodies in the blood of the recipient; in addition, repeated blood transfusions can depress the immune function in the host. This is one of the reasons why an artificial blood substitute is highly desirable since it can avoid these complications. Two main approaches are used for achieving an artificial blood substitute, bio- artificial oxygen carriers and totally synthetic oxygen carriers. Bio-artificial oxygen carriers are hemoglobin-based oxygen carriers and use human, animal, or recombinant hemoglobin. Synthetic oxygen carriers use metal chelates that mimic the hemoglobin’s oxygen binding capacity. Artificial fluorinated organic compounds can physically dissolve large amounts of oxygen, perflurocarbon- based oxygen carriers are commonly employed for this purpose. However, in a strict sense they constitute oxygen carrier substitutes and not blood substitutes since they lack the coagulation factors and immune cells fighting infection that are essential in aiding coagulation and clot formation and fighting infection, which can be vital in the patients receiving these therapies. Examples of bio-artificial oxygen carriers include modified human or animal hemoglobin-based carriers, stabilized hemoglobin tetramers, polymerized hemoglobin, conjugated hemoglobin, and liposome encapsulated hemoglobin. Other carriers also include recombinant hemoglobin or from transgenic studies. Synthetic oxygen carriers include lipid–heme vesicles, hemoglobin aquasoms, and perflurocarbonbased carriers. More detailed reviewispresented elsewhere (Kim and Greenburg, 2004). Bar-Cohen : Biomimetics: Biologically Inspired Technologies DK3163_c018 Final Proof page 463 21.9.2005 3:40am Artificial Support and Replacement of Human Organs 463 18.14 OTHER SUBSTITUTES The last few decades have seen an explosive growth in the development of various implants such as pacemakers, stents for the arteries, cochlear implants (Rubinstein, 2004) to improve hearing, apheresis, small joints for the fingers and other joints, etc., the list is quite long and a brief review like this is unable to cover these areas in detail. Another field that is currently undergoing intense research is the field of xenotransplantation. Theoretically, this should allow transplantation of organs from animals to humans; however, there are several issues which need to be addressed include the risk of transmission of animal diseases to humans, the altered immune response that may accompany the species specific difference (Hammer, 2004; Schmidt et al., 2004). 18.15 LIMITATIONS OF THE CURRENT ORGAN REPLACEMENT SYSTEMS In spite of the significant advances made in the development of the artificial organs, some common problems plague all the systems. Biocompatibility (Hernandez et al., 2004; Jalan et al., 2004) is still a major problem, necessitating heparinization to avoid thrombosis. The use of heparin, to combat thrombosis, puts the patient at risk of bleeding-associated complications (Boyle et al., 2004; Minami et al., 2000; Rose et al., 2001). The organ systems do not truly replace the organs except in the case of total artificial heart. Most of the systems work on the principle of passive transport as in artificial kidney, artificial liver, and lung and hence fail to mimic the physiological functions of these individual organs. Most of these systems expose the body to increased infection risk due to the various lines and ports used for access (Rose et al., 2001; Tobin and Bambauer, 2003). This risk of infection can be serious in an already sick group of patients (El-Banayosy et al., 2001; Minami et al., 2000). Other limitations include nonphysiological support; for example, the organ support in case of kidneys need not be continuous as is the case of normal kidney which carries out the work 24 h a day, and this can disturb the delicate physiological balance necessary for the optimum biological function- ing. Mobility is restricted in all types of the support devices. The issue of energy supply is very important in the case of artificial ventricular assist devices and the artificial heart; these devices need to work continuously and lack of back-up systems can be catastrophic (Portner, 2001). Mechanical failure is an important issue if long term support is envisaged. 18.15.1 Impact of Other Technologies Technological advances are rapidly taking place around us and it is natural that these will significantly affect future organ support systems. The current organ replacement systems were designed in the 1960s and 1970s; it is a natural evolutionary step that new technology will replace the older systems. In concluding this section, we will take a glimpse at current developmental research in related fields and how it will impact the future of organ replacement systems. 18.15.1.1 Tissue Engineering Tissue engineering is a science that uses living cells combined with biomaterials for diagnostic and therapeutic purposes. This involves generation of cells, tissues, and complex organoid structures in the laboratory to replace natural organ function partially or completely (Fuchs et al., 2001). Application of tissue engineering has resulted in the development of bio-artificial kidney (Aebischer et al., 1987), liver (Chamuleau, 2002; Kulig et al., 2004), tissue-engineered heart valves (Hoerstrup et al., 2000a,b; Stock et al., 2002) and generation of myocardial cells to treat Bar-Cohen : Biomimetics: Biologically Inspired Technologies DK3163_c018 Final Proof page 464 21.9.2005 3:40am 464 Biomimetics: Biologically Inspired Technologies heart failure (Thompson et al., 2003). From the initial euphoria in 1990 to disappointment in 2004, tissue engineering has been put to test; a number of products have not shown benefit in clinical trials, that in turn is reflected in the lack of market interest in these products (Lysaght and Reyes, 2001; Lysaght and Hazlehurst, 2004). Tissue engineering has the necessary potential of seeding appropriate scaffolding with cells of interest as in the case of tubule cells used in artificial kidney (Fey-Lamprecht et al., 2003; Humes, 2000; Ozgen et al., 2004). As our understanding increases in terms of cell growth characteristics in relation to biomaterials, we are likely to move towards bio-artificial organ replacement systems. Normal organs, however, are composed of many different cell types with complex messaging and interactions. Using a single cell type may not necessarily guarantee adequate functioning of such systems. The importance of developing appropriate scaffolds for the blood vessels to grow can be key to future development of solid organs (Kaihara et al., 2000; MacNeill et al., 2002). The current systems use altered cancerous cells or cells from animal origin, which raises the likelihood of risk of cancerous transformation and transmission of animal originated diseases (van de Kerkhove et al., 2004). However, using adult stem cells from the patients’ own bone marrow may be the solution which will be more widely applied in the future. 18.15.1.2 Stem Cell Technology Stem cells are the precursor cells from which any type of cell differentiation is possible (Jain, 2002). There are two types of stem cell sources that can be used, one from the embryonic stage and another from the adult stem cells within the bone marrow. Stem cells from the embryonic stage offer the characteristic of differentiating into any possible cell type (Kakinuma et al., 2003; Sukhikh and Shtil, 2002); but recent findings, however, of increasing plasticity shown by the human hematopoietic stem cells to differentiate into different cell types has led to interest in developing them as a cell therapy for organ failure (Liu et al., 2004a–c; Schuster et al., 2004; Strom et al., 2004; Yokoo et al., 2003). 18.15.1.3 Impact of Understanding the Human Genome The human genome sequence now has been decoded (Venter et al., 2001). This offers the potential of synthetic DNA which can create proteins of interest. Theoretically, this can be used to develop synthetic organ systems and conceivably a complete organism. However, there are several limita- tions to this concept since we still do not have the insight into the function and role of all the human genes. Early indications suggest a possibility of tailor-made treatment based on the individual patient’s genomic characteristics; how this will apply to the treatment and replacement of organ systems remains to be fully explored. 18.15.1.4 Microelectromechanical Systems Microdevices have been applied for certain diagnostic, therapeutic, and selected surgical proced- ures (Evans et al., 2003; Polla et al., 2000; Richards Grayson et al., 2004). Microelectromechanical systems (MEMS) employ the same manufacturing methods as silicone chips for computer industry. They can be a useful tool for rapid screening of diseases, measurement of blood levels of hormones and drugs, targeted drug delivery, and novel micro-stimulators in neurosciences (Evans et al., 2003; Huang et al., 2002; Liu et al., 2004a–c; Polla et al., 2000; Roy et al., 2001). What makes MEMS more promising is the building of small rotors capable of running on miniscule energy (Epstein and Senturia, 1997; Miki et al., 2003). These have enormous potential to provide the energy source for organ replacement systems. In addition, they can provide the capability to detect the minute changes in hormones and endorphins on which the response of the organ support system can be tailored. Bar-Cohen : Biomimetics: Biologically Inspired Technologies DK3163_c018 Final Proof page 465 21.9.2005 3:40am Artificial Support and Replacement of Human Organs 465 18.15.2 Nanotechnology and Biomimetics Living organisms are the perfect example of the advanced nanotechnological manufacturing by nature. What could be more interesting than trying to build artificial organs from the beginning and mimicking nature? Advances in the development of artificial organs to date have relied mainly on supplanting the function of an organ with an alternative process. As in the case of heart, it is the pumping mechanism, in lungs the oxygenation of the blood, and in liver and kidney, the removal of harmful wastes. But biological organs play even more complex and dynamic role in the physiological mileu in terms of metabolic and other organ function. The biofeedback in these natural organs takes place at nano-dimensions, which the present replacement systems are unable to mimic precisely enough to bring about changes in the functionality of the devices. Nanotechnology can provide molecularly manipulated nanostructured materials which will mimic the natural surfaces. Sensing and control can be achieved in these systems using microelec- tronics and novel interface technologies (Lee et al., 2004). Drug delivery systems at nanoscale can maintain the function of normal cells (Prokop, 2001). Molecular self-assembly can simulate the surface geometry by polymeric patterning; since this has immense importance in the behavior of the individual cell and cell to cell communication, adhesion and migration (Chaikof et al., 2002; Hilt, 2004). Current cell and tissue culture systems fail to mimic the natural processes that provide extracellular matrix. Extracellular matrix plays an important role in the repair processes and thus influences cell behavior and survival. Scaffolds at a micro-level can be created using nanotechnol- ogy, and can incorporate the extracellular matrix containing glycosaminoglycans and glycoproteins supporting cell growth and proliferation (Bouhadir et al., 2001; Chaikof et al., 2002). The advances in nanotechnology allow us to synthesize novel materials, fabricate them in two or three-dimensional forms as scaffolds and allow the growth of new cells and ultimately whole organs (Chaikof et al., 2002; Karlsson et al., 2004; Moldovan and Ferrari, 2002). The National Institute of Health (NIH) has taken a big initiative in funding nanomedicine- related research and development. The NIH roadmap aims to have applications in drug delivery, cell repair, anticancer methodologies, and biomachines that could remove and replace a damaged cell or tissue. The biggest advantage of nanotechnology will be in understanding the organ function at minute levels and creating bio-engineered cells and tissues capable of replacing human organs. Structural and functional creation of artificial organs using nanotechnology will need precise understanding of the structure and function of the organ; the current knowledge of anatomical structures can greatly help in this regard. This can allow bioengineers to create exact scaffolds for the blood vessels and cells to grow. The issue of energy source can only be solved, however, if micro-machines are built which can derive energy from oxygen, glucose and other substances that are easily available in the body. 18.16 SUMMARY The current emphasis on replacement by mechanical systems is already profoundly affected by newer technologies. In the future, bio-compatible surfaces will be designed keeping in mind the precise interactions at atomic and molecular levels rather than the trial-and-error approach that was adopted several decades ago. These newer technologies will definitely have an impact on future artificial medical implants, be it artificial heart valves, vascular conduits, or artificial organ systems. Design and technology will certainly move to center stage in the coming years. Unique problems will be posed for the today’s scientists, physicians, and engineers, who are slow to adjust to collaborative research. Current funding structure is limited in supporting such collaborations; the cost of such design and manufacturing will be prohibitive for one group or individual organizations Bar-Cohen : Biomimetics: Biologically Inspired Technologies DK3163_c018 Final Proof page 466 21.9.2005 3:40am 466 Biomimetics: Biologically Inspired Technologies to sustain. Answers to these problems will hopefully be addressed in the future federal funding mechanism as outlined in the initiative by NIH on nanotechnology. One of the questions that is frequently debated is whether future organ replacement technology will involve miniaturizing the current systems or building newer organ replacement systems from scratch. As outlined above, current organ replacement systems have several disadvantages which will be difficult to overcome even if they are miniaturized. Miniaturization will certainly play an important role in devising therapeutic interventions such as drug delivery. Devising organ replacement systems from scratch will help address the current problems of biocompati- bility and better mimic the organ function at cellular level. This will involve creating novel anatomical models of scaffoldings which are biocompatible and bioactive to allow cell growth and differentiation so that complex organs can be developed. Such new organ systems will need to produce energy from oxygen, glucose, and other substances freely available in the blood and be self-sufficient. How far we are from the reality of buying off-the-shelf artificial organs? May be in next 10 years? As the pace of developments in the fields of nanotechnology, tissue engineering, and others is accelerating, the reality of having a self-sustaining artificial organ replacement system is a possible reality in the upcoming years. REFERENCES Aebischer, P, Ip, TK, Panol, G, et al. The bioartificial kidney: progress towards an ultrafiltration device with renal epithelial cells processing, Life Support Syst, 5, 2, 1987, 159–68. AHA. Heart Disease and Stroke Statistics: 2004 Update, American Heart Association, Dallas, TX, 2003. Akustu, T and Kolff, WJ. Permanent substitute for valves and hearts, Trans Am Soc Artif Intern Organs,4, 1958. Anderson, R and Smith, B. 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Bar-Cohen : Biomimetics: Biologically Inspired Technologies DK3163_c018 Final Proof page 471 21.9.2005 3:40am Artificial Support and Replacement of Human Organs 471 [...].. .Bar- Cohen : Biomimetics: Biologically Inspired Technologies DK3163_c018 Final Proof page 4 72 21.9 .20 05 3:40am 4 72 Biomimetics: Biologically Inspired Technologies Still, J, Glat, P, Silverstein, P, et al The use of a collagen sponge/living cell composite material to treat donor sites in burn patients, Burns, 29 , 8, 20 03, 8 37 41 Stock, UA, Vacanti, JP, Mayer, JE,... corn grits (B, grits are particles of broken seed endosperm) The final volume increase is about 150% in split pea seeds and 20 0% in corn seed particles Note that the smaller grit particles hydrate much faster than the larger peas Bar- Cohen : Biomimetics: Biologically Inspired Technologies DK3163_c019 Final Proof page 478 21 .9 .20 05 8:02pm 478 Biomimetics: Biologically Inspired Technologies teacher’s demonstration... regrowing root and root-like haustoria However, translocation of individuals occurs frequently in some developmental stages of lower plants and in motile single-celled and multicellular algae Botanists call this type of individual 473 Bar- Cohen : Biomimetics: Biologically Inspired Technologies DK3163_c019 Final Proof page 474 21 .9 .20 05 8:02pm 474 Biomimetics: Biologically Inspired Technologies movement... Ther, 3, 5, 20 03, 3 87 94 Zimmer, HG Perfusion of isolated organs and the first heart–lung machine, Can J Cardiol, 17, 9, 20 01, 963–9 Zwischenberger, JB, Anderson, CM, Cook, KE, et al Development of an implantable artificial lung: challenges and progress, Asaio J, 47, 4, 20 01, 31 6 -2 0 Bar- Cohen : Biomimetics: Biologically Inspired Technologies DK3163_c019 Final Proof page 473 21 .9 .20 05 8:02pm 19 Nastic... 1953) As in human-made inflatable structures (e.g., sleeping bags) pressurization of the cells leads to the expansion as well as stiffening and hydrostatic stabilization of the cells, tissues, and entire structures (e.g., Niklas, Bar- Cohen : Biomimetics: Biologically Inspired Technologies DK3163_c019 Final Proof page 476 21 .9 .20 05 8:02pm 476 Biomimetics: Biologically Inspired Technologies 19 92) To prevent... 473 19 .2 Motors in Nature’s Nastic Designs 474 19 .2. 1 Osmotic Motors 475 19 .2. 2 Colloid-Based Motors 476 19 .2. 2.1 Macroscopic Swelling Bodies 477 19 .2. 3 Fibrous Motors 479 19.3 Nastic Structures in Plants 481 19.3.1 Hydrostat Motor Cells — Source and Location of Movements 4 82 19.3 .2 From Isotropic Cell... 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(Walter, 19 57) This high degree of hydration is not osmotic but due to the presence of adsorptive forces (called adhesion or imbibition) that can equal and exceed the pressure of osmotic systems by reaching values of up to Bar- Cohen : Biomimetics: Biologically Inspired Technologies DK3163_c019 Final Proof page 477 21 .9 .20 05 8:02pm Nastic Structures: The Enacting and Mimicking of Plant Movements 477 100 MPa . progress, Asaio J, 47, 4, 20 01, 31 6 -2 0. Bar- Cohen : Biomimetics: Biologically Inspired Technologies DK3163_c018 Final Proof page 4 72 21.9 .20 05 3:40am 4 72 Biomimetics: Biologically Inspired Technologies 19 Nastic. Presbyterian 1 2- year experience, J Thoracic Cardiovasc Surg, 1 27 , 5, 20 04, 1309–16. Bar- Cohen : Biomimetics: Biologically Inspired Technologies DK3163_c018 Final Proof page 470 21 .9 .20 05 3:40am 470 Biomimetics: . relevant bone levers. 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