Endeavors of Chemical Engineering: Artificial Organ Pranshu sharma, Rishabh chaudhary

USCT DELHI, USCT DELH, GGSIPU INDIA, GGSIPU INDIA

Pranshu22@gmail.com

rishabh_chaudhary@hotmail.com

Abstract—One of the most significant frontiers of Chemical engineering is Biomedicine and chemical engineers have made some of their greatest achievements in this field. This paper states and elucidates the contribution of chemical engineers in development of artificial organs and engineering challenges faced by them in this endeavor. More specifically the paper deals with the role of chemical engineering in development of Heart and Lung Machine, Artificial Kidney.

Keywords—artificial organs, heart-lung machine, artificial kidney.

INTRODUCTION

It is very logical to think of human body as a complex and sensitive chemical factory with a number of heat and mass transfer processes going on, sometimes accompanied with chemical reactions. Muscles shiver to warm the body when the temperature falls. The pancreas produces insulin to control blood sugar levels. The kidneys remove urea, minerals, and water from the blood. White blood cells organize themselves to defend the body against infection. These need to be controlled to ensure the working of body.

Efforts to understand and view humans as a collection of interrelated “chemical” systems began in the mid-1800s, when Claude Bernard, a French physician and physiologist, helped introduce the rigors of the scientific method to medicine such as • establishing the role of the pancreas in controlling digestion, • determining the glycogenic function of the liver (which later helped understand the critical roles played by glucose and insulin in regulating vital bodily processes), and • demonstrating that nerves could either expand or constrict blood vessels, a breakthrough that helped understand the vasomotor system (vaso refers to blood vessels).

Over the last half century, chemical engineers have contributed to various biomedical endeavors. They have helped modernize disease diagnosis and treatment options, improve the safety and efficacy of drug delivery mechanisms, and achieve better therapeutic outcomes, resulting in longer, healthier, more productive lives for patients. It was in 1970s when chemical engineers first started to analyze mass transfer phenomenon and rheological issues related to artificial organs for example, diffusion rates through biomembranes. A growing number of chemical engineers were engaged in solving complex flow problems—related to, among other things, heart valves—by using Newtonian fluid-mechanics analysis. (Newtonian fluids flow like water, while non-Newtonian fluids are those whose viscosity, or ability to flow, changes as the applied rate of strain changes.)

HEART and LUNG MACHINE

Coronary bypass surgery, widely used to treat cardiovascular disease, involves redirecting a patient’s bloodflow around the heart in order to allow surgeons to operate. Heart-lung machines synthetically oxygenate and pump blood during such surgeries in order to keep the patient alive. The first heart-lung machine dates back to the 1930s and consisted of many of the same components as the machines of today. The design of each of these components is inspired by different principles of physics and engineering, including fluid dynamics and pressure gradients. Engineers are now applying these same concepts to create new heart-lung machine models such as miniaturized or portable versions. With its foundations in biology, physics, and engineering, the heart-lung machine has proven to revolutionize the treatment of heart disease.

Historical Background

The first machine of this type was developed by surgeon John Heysham Gibbon in the 1930s [2]. During this time, physicians were looking into the possibility of extracorporeal circulation, or blood flow outside of the body [3]. They wondered if there was a way to extend this extracorporeal circulation to bypass not just minor organs, as was often done in surgery at the time, but to bypass the heart completely. Saddened at a patient’s death mid-surgery, Gibbon made it his mission to come up with an artificial heart-lung machine that would keep a patient alive during heart surgery.

Fig 1 a) John Gibbon, Jr. b) Heart-Lung Machine

Between 1934 and 1935, Gibbon built a prototype of his heart-lung machine and tested its function on cats in order to assess what problems needed to be addressed before using it with humans [4]. For example, in one model Gibbon observed that an inadequate amount of bloodflow was exiting the machine, so he decided to make the flow continuous, instead of in short pulses [4]. By introducing bloodflow that would remain at the same rate continuously, instead of increasing and decreasing with a set rhythm, he increased the total blood volume capacity that could flow throughout the machine.

In the 1940s, Dr. Gibbon met Thomas Watson, an engineer and chairman of International Business Machines (IBM). Gibbon and Watson, along with other engineers from IBM, collaborated on the quest for an effective cardiopulmonary bypass machine, and together they created another new model [2]. When this model was testing by performing surgeries on dogs, they noticed

that many of their test subjects died after surgery due to embolisms (An embolism occurs when a small particle or tissue migrates to another part of body and causes the blockage of a blood vessel, which prevents vital tissues from receiving oxygen) [5]. From these experiments, they saw the need to add a filter to their apparatus. Gibbon and the IBM engineers decided to use a 300-micron by 300-micron mesh filter, which proved successful in trapping these harmful tissue particles [4].

In 1953, Gibbon himself completed the first successful surgery on a human patient with the help of the cardiopulmonary bypass machine [6]. Since then, open heart surgeries have been performed for over 55 years, with almost 700,000 performed annually in recent years [1]. Much has changed since Gibbon’s first model, but the main engineering concepts behind his machine have remained the same. Today’s heart-lung-machine contains the same basic components: a reservoir for oxygen-poor venous blood, an oxygenator, a temperature regulator, a pump to drive the blood flow back to the body, a filter to prevent embolisms, and connective tubing to tie all the other elements together [4].

Fig 1 Representation of Heart Lung Machine

Working of Heart Lung

To function, the heart lung machine must be connected to the patient in a way that allows the blood to be removed, processed and returned to the body. Therefore, it requires two hook-ups. One is to a large artery where fresh blood can be pumped back into the body. The other is to a major vein where “used” blood can be removed from the body and passed through the machine.

In fact, connections are made on the right side of the heart to the inferior and superior vena cavae (singular: vena cava). These vessels collect blood drained from the body and head and empty into the right atrium. They carry blood that has been circulated through the body and is in need of oxygenation. Another connection is made by shunting into aorta, the main artery leading from heart to the body, or the femoral artery, a large artery in the upper leg. Blood is removed from the vena cavae, passed into the heart lung machine where it is cooled to lower the patient’s body temperature, which reduces tissues’ need for blood. The blood receives oxygen which forces out carbon dioxide and it is filtered to remove any detritus that should not be in circulation such as small clots. The processed blood then goes back into the patient in the aorta or femoral artery.

During surgery the technician monitoring the heart lung machine carefully watches the temperature of the blood, the pressure at which it is being pumped, its oxygen content, and other measurements. When the surgeon nears the end of the procedure the technician will increase the temperature of the heat exchanger in the machine to allow the blood to warn. This will restore the normal body heat to the patient before he is taken off the machine.

Major Challenges in Design

The machine made by Dr. Gibbon required many pints of blood to prime the machine and it was bulky and took up much of the room in the operating room.

Clotting in oxygenator films due to inadequate heparinization.

Maintaining adequate bloodflow.

Today’s Machines

In an open-heart surgery, the surgeon first connects the bypass machine to the patient by inserting tubes called the venous cannulas into the vena cavae, the large blood vessels leading to the heart [7]. This redirects the flow of blood into the heart-lung machine, bypassing the heart completely. Engineers must design the venous cannulas such that a precise and controlled amount of blood will flow through them into the machine. They do so by creating the tubes in varying sizes and resistances [8]. According to fluid dynamic principles, the larger a tube is, the more liquid can flow through it at a given point in time. On the other hand, if a tube has a greater resistance, which is controlled

by surface roughness and fluid viscosity, then less fluid may pass through. By adjusting these two properties, an engineer can create venous cannulas that allow specific rates of blood to flow from the body and into the machine.

From the cannulas, the blood flows into the venous reservoir, a chamber made of plastic or polyvinyl chloride (PVC) that collects and stores the blood from the patient’s body [9]. The reservoir must have a large volume capacity to accommodate a large volume of blood. According to Boyle’s Law, pressure and volume are inversely related under constant temperature; as one increases, the other decreases. Thus, the venous reservoir’s large volume gives it a low pressure. All solvents naturally move from regions of higher pressure to regions of lower pressure. Therefore, since the reservoir has a low pressure, blood flows from the high-pressure vessels in the body into the bypass machine’s venous reservoir.

Upon leaving the venous reservoir, blood next travels into the heart-lung machine’s pump, which utilizes compression force or centrifugal force to drive blood flow. A pump may come in either one of two types: roller pumps or centrifugal pumps. In a roller pump, the blood enters a curved track of tubing made of a flexible material, often PVC, latex, or silicone [8]. As the blood enters, two cylindrical rollers rotate and slide forward, constricting the tubing. This compression reduces the volume in the tube, giving the blood no room to go but forward. Just as squeezing a tube of toothpaste pushes the paste forward and out of the tube, compressing the roller pump forces the blood to flow forward, through the rest of the bypass machine. While roller pumps may be used as the primary pump in a heart-lung machine, centrifugal pumps are often used as an alternative. The centrifugal pump is comprised of a plastic wheel that rotates rapidly, propelling the liquid away from the center of rotation [8]. Imagine spinning a bucket of water overhead fast enough so that water is pressed outward against the bucket and does not fall out. The same force is utilized in the heart-lung machine as the rotation of the centrifugal pump forces the blood to flow past the spinning wheel and out towards the next section of tubing. While some heart-lung machine manufacturers prefer this type of pump because they believe it reduces the formation of harmful clotting elements in the blood, at this point in time, both types of pumps are widely used [10].

Blood flows from the pump into the heat exchanger, which uses the concept of heat transfer to cool the blood down to the optimal temperature for surgery. The human body normally maintains an internal temperature of 37 degrees Celsius but during cardiac surgery, physicians lower the patient’s core temperature to a state of moderate hypothermia or 5 to 10 degrees lower than usual [8]. Oxygen gas is more soluble in cold blood than in warm blood [11]. Thus, lowering the temperature maximizes the amount of oxygen the patient’s blood cells can carry.

Following the basic principle of heat transfer, a warmer object will always transfer heat to any colder object with which it is in contact. Similarly, if a cold object touches a warmer object, the warmer object will be cooled. That is precisely what occurs in the heart-lung machine’s heat exchanger. It consists of a thermally adjustable compartment of cold water with plastic rubes submerged in it. As blood flows through the tubes, thermal energy is transferred between the water and the tubing, and then between the tubing and the blood. The warmer object, the blood, becomes colder, while the cooler object, the water, becomes warmer. Thus, the heat exchanger cools the blood to the desired temperature.

From the heat exchanger, the cooled blood enters the oxygenator, where it is imbued with oxygen. Today’s heart-lung machines use an oxygenator that attempts to mimic the lung itself. This oxygenator, aptly called a membrane oxygenator, consists of a thin membrane designed like the thin membranes of the alveoli, the air-filled sacs that comprise the lungs. Venous blood from the heat exchanger flows past one side of the membrane, while oxygen gas is stored on the other. Micropores in the membrane allow oxygen gas to flow into the blood and into the blood cells themselves. Just as blood spontaneously flows along a pressure gradient, gases also move from regions of high pressure to regions of low partial pressure. The oxygenator is designed such that the oxygen pressure on the gas side of the membrane is much higher than the pressure in the blood [12]. Thus, oxygen passes through the membrane into the blood, following the natural high-to-low pressure gradient.

At this point in the journey through the heart-lung machine, the blood has been collected, cooled and oxygenated, so it is nearly ready to return to the patient’s body. Before this can happen,

however, it must pass through a filter to eliminate the potential for embolisms. Anything that could lead to blockage of a blood vessel, whether it is an air bubble, a piece of synthetic material, or a clotting protein, poses a great risk to the patient and must be filtered out of the returning blood. The filters used in the heart-lung machine are comprised of nylon or polyester thread woven into a screen with small pores [8]. The small pores trap the harmful bubbles or particles, allowing purer blood, free from dangerous embolism-causing particles, to flow through. After being filtered, the blood travels through plastic tubes called arterial cannulas. Arteries, the blood vessels that deliver oxygen-rich blood from the heart to the rest of the body, have the highest speed of any vessel. In order to imitate this, engineers designed the arterial cannulas to be very narrow [8]. In fluid dynamics, the flow rate of a liquid through a vessel is equal to the cross-sectional area times the speed of flow. Thus, tubes like the arterial cannulas that have a smaller diameter allow for a higher blood velocity. During surgery, the physician inserts the cannulas into one of the major arteries of the patient, such as the aorta or the femoral artery [7]. Blood then leaves the last component of the cardiopulmonary bypass machine, enters the patient’s own vessels, and again makes its natural journey through the circulatory system.

Heart Machines of Future

Recent breakthroughs of biomedical engineers give a glimpse of the cardiopulmonary bypass machines of the future. In 2007, the world’s first portable heart-lung machine received the CE mark, which officially allowed it to be sold across Europe. Weighing only 17.5 kilograms and powered by a rechargeable battery, the Lifebridge B2T can be transported to different parts of a hospital, giving paramedics or emergency room physicians the chance to start extracorporeal circulation in critical patients before even reaching the operating room [13] (Fig. 2).

European Hospital/European Hospital

Figure 2: The compact 17.5 kg heart-lung machine Lifebridge B2T.

Another new development of the heart-lung machine is the MiniHLM, a miniaturized heart-lung machine developed for infants. Instead of having all the components spaced separately, as with normal-sized machines, the MiniHLM integrates the functions so the machine is much smaller and more compact [13]. This allows cardiac bypass surgery to be performed on neonates, something that will surely expand the capacity with which heart conditions in newborns can be treated.

Current implementations of the cardiopulmonary bypass machine have advanced far past John Gibbon’s original idea almost 80 years ago. Yet no step in the process has been insignificant, as every improvement has improved the safety and usability of the machine. Engineers continue to consider both the biological needs of the human body and the basic principles of physics in order to create a functional biocompatible device that performs what was once unthinkable, sustaining human life without the use of one’s heart or lungs. Hundreds of thousands of patients undergo open-heart bypass surgeries every year, intense procedures which require extracorporeal circulation [14]. That’s hundreds of thousands of lives saved with the help of one essential biomedical device: the heart-lung machine.

ARTIFICIAL KIDNEY MACHINE

Kidneys

Kidneys are paired vital organs located behind the abdominal cavity, at about the level of the bottom of the ribcage. They perform about a dozen physiologic functions, and are fairly easily damaged.

Fig.3 1. Renal pyramid • 2. Interlobular artery • 3. Renal artery • 4. Renal vein 5. Renal hilum • 6. Renal pelvis • 7. Ureter • 8. Minor calyx • 9. Renal capsule • 10. Inferior renal capsule • 11. Superior renal capsule • 12. Interlobular vein • 13. Nephron • 14. Minor calyx • 15. Major calyx • 16. Renal papilla 17. Renal column

Function of Kidneys

1. Excretion of wastes

The kidneys excrete a variety of waste products produced by metabolism. These include the nitrogenous wastes called "urea", from protein catabolism, as well as uric acid, from nucleic acid metabolism. Formation of urine is also the function of the kidney. The concentration of nitrogenous wastes, in the urine of mammals and some birds, is dependent on an elaborate countercurrent multiplication system. This requires several independent nephron characteristics to operate: a tight hair pin configuration of the tubules, water and ion permeability in the descending limb of the loop, water impermeability in the ascending loop and active ion transport out of most of the ascending loop. In addition, countercurrent exchange by the vessels carrying the blood supply to the nephron is essential for enabling this function.

2. Acid-base homeostasis

Two organ systems, the kidneys and lungs, maintain acid-base homeostasis, which is the maintenance of pH around a relatively stable value. The lungs contribute to acid-base homeostasis by regulating carbon dioxide (CO2) concentration. The kidneys have two very important roles in maintaining the acid-base balance: to reabsorb bicarbonate from urine, and to excrete hydrogen ions into urine

3. Osmolality regulation

Any significant rise in plasma osmolality is detected by the hypothalamus, which communicates directly with the posterior

pituitary gland. An increase in osmolality causes the gland to secrete antidiuretic hormone (ADH), resulting in water reabsorption by the kidney and an increase in urine concentration. The two factors work together to return the plasma osmolality to its normal levels.

ADH binds to principal cells in the collecting duct that translocate aquaporins to the membrane, allowing water to leave the normally impermeable membrane and be reabsorbed into the body by the vasa recta, thus increasing the plasma volume of the body.

There are two systems that create a hyperosmotic medulla and thus increase the body plasma volume: Urea recycling and the 'single effect.'

Urea is usually excreted as a waste product from the kidneys. However, when plasma blood volume is low and ADH is released the aquaporins that are opened are also permeable to urea. This allows urea to leave the collecting duct into the medulla creating a hyperosmotic solution that 'attracts' water. Urea can then re-enter the nephron and be excreted or recycled again depending on whether ADH is still present or not.

The 'Single effect' describes the fact that the ascending thick limb of the loop of Henle is not permeable to water but is permeable to NaCl. This allows for a countercurrent exchange system whereby the medulla becomes increasingly concentrated, but at the same time setting up an osmotic gradient for water to follow should the aquaporins of the collecting duct be opened by ADH.

4. Blood pressure regulation

Although the kidney cannot directly sense blood, long-term regulation of blood pressure predominantly depends upon the kidney. This primarily occurs through maintenance of the extracellular fluid compartment, the size of which depends on the plasma sodium concentration. Renin is the first in a series of important chemical messengers that make up the renin-angiotensin system. Changes in renin ultimately alter the output of this system, principally the hormones angiotensin II and aldosterone. Each hormone acts via multiple mechanisms, but both increase the kidney's absorption of sodium chloride, thereby expanding the extracellular fluid compartment and raising blood pressure. When renin levels are elevated, the concentrations of angiotensin II and aldosterone increase, leading to increased sodium chloride reabsorption, expansion of the extracellular fluid compartment, and an increase in blood pressure. Conversely, when renin levels are low, angiotensin II and aldosterone levels decrease, contracting the extracellular fluid compartment, and decreasing blood pressure.

5. Hormone secretion

The kidneys secrete a variety of hormones, including erythropoietin, and the enzyme renin. Erythropoietin is released in response to hypoxia (low levels of oxygen at tissue level) in the renal circulation. It stimulates erythropoiesis (production of red blood cells) in the bone marrow. Calcitriol, the activated form of vitamin D, promotes intestinal absorption of calcium and the renal reabsorption of phosphate. Part of the renin-angiotensin-aldosterone system, renin is an enzyme involved in the regulation of aldosterone levels

Renal Failure

Kidney failure results in the slow accumulation of nitrogenous wastes, salts, water, and disruption of the body's normal pH balance. Until the Second World War, kidney failure generally meant death for the patient. Several insights into renal function and acute renal failure were made during the war, not least of which would be Bywaters and Beall's descriptions of pigment-induced nephropathy drawn from their clinical experiences during the London Blitz.[17]

Hemodialysis

Hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water from the blood when the kidneys are in renal failure. The mechanical device used to clean the patient’s blood is called a dialyser, also known as an artificial kidney. One of the ten wonders

In 1964 Les Babb, a chemical-biochemical engineer, along with his colleagues at the University of Washington, designed a portable, fail-safe, single-patient dialysis machine. Within five years this stand-alone machine would become the dialysis system of choice throughout the world. In 1990 the Biomedical Engineering Society named this machine one of the “Ten Wonders of Biomedical Engineering.” [18]

Artificial Kidney

Artificial kidney is often a synonym for hemodialysis, but may also, more generally, refer to renal replacement therapies (with exclusion of renal transplantation) that are in use and/or in development. This article deals with bioengineered kidneys/bioartificial kidneys that are grown from renal cell lines/renal tissue.

Modern dialysers typically consist of a cylindrical rigid casing enclosing hollow fibers cast or extruded from a polymer or copolymer, which is usually a proprietary formulation. The combined area of the hollow fibers is typically between 1-2 square meters. Intensive research has been conducted by many groups to optimize blood and dialysate flows within the dialyser, in order to achieve efficient transfer of wastes from blood to dialysate.

Fig.4 Dialyser used in hemodialysis

Gordon Murray and the artificial kidney

Introduction :

Few people even amongst nephrologists are aware that Canadian surgeon Gordon Murray (1894–1976) built the first North American artificial kidney, independently of work by Willem Kolff in the Netherlands and Nils Alwall in Sweden at about the same time. Perhaps this is because Kolff is generally recognized as the `inventor' of the artificial kidney in a clinically useful form, whereas Murray's fame, publicly and professionally, came from his work in cardiovascular surgery.

Murray became interested in renal therapy during the 1940s after seeing several patients die of uraemia [19]. Frustrated by the profession's ignorance of this disease, he began investigating the kidney with the prospect of mechanically replicating its functions and in the end he built two different artificial kidney machines. His first successful artificial kidney was a coil design built in 1945–46, with the assistance of Edmund Delorme, a young surgeon from the University of Edinburgh, and Newell Thomas, an undergraduate chemistry student at the University of Toronto. In 1952–53, a second-generation flat-plate model was designed and constructed by Murray and scientist Dr Walter Roschlau, originally from Heidelberg. Unfortunately, these artificial kidneys remained relatively crude prototypes, and were never refined or commercially produced for wider distribution.

Fig.5 Gordon Murray

Murray's first artificial kidney machine (1945–46)

As no one had yet designed and used an `artificial kidney' when he began his experiments, Murray encountered several technical difficulties in the building of his first machine: discovering a suitable dialysing membrane, finding the proper dialysing solution or dialysate, and selecting a viable mechanism for circulating blood through the machine. The dialysing membrane that led the blood through the dialysate had to be a semi-permeable membrane to allow the molecules of harmful wastes to pass into the dialysate. After experimenting with various natural and synthetic products and following the work of William Thalhimer in New York [20], Murray found (like Kolff) that the best semi-permeable membrane was a type of Cellophane used for sausage casing in the form of long tubes. He experimented with the size and length of tubing before settling for the satisfactory size of ¼ in (6.5 mm) diameter, varying in length from 35 to 150 feet (10–50 m). The tubing was coiled vertically around a wire-mesh cylinder and contained in a large bath jar or drum filled with the dialysate. Next, Murray sought a dialysate consistent with the normal substances of the blood. Finally, after a number of false starts, he settled on using Ringer's solution. To circulate the blood through the machine, Murray decided to work exclusively within the venous system, taking blood from and returning it to a vein, using a novel atraumatic pump system (in contrast to arteriovenous circuiting chosen by other pioneering researchers, notably Kolff and Nils Alwall). A rubber tambour was inflated and deflated by the action of the piston-syringe, acting as the pump, attached to an electric motor. Intake and outlet valves controlled the blood flow. Tinkering away with relative simple materials at hand, Murray completed the building of his prototype machine [21]

Fig.6. Murray's first dialyser, a coil design wound on a steel frame (left). Note the narrow calibre of the blood tubing, which was only 6 mm wide, but up to 50 m long. Also shown is Murray's atraumatic blood pump (centre), which allowed venovenous dialysis.

History of Murray’s Experiment

To test his artificial kidney, Murray first ran trials with uraemic animals, treating them for hours, even overnight, with relative success. The real test, however, came with Murray's first clinical case in December 1946. A 26-year-old female patient lay in a uraemic coma at the Toronto General Hospital as a result of an abortion attempt. Her doctors declared her case hopeless, and they called Murray. They were not terribly convinced that the artificial kidney would actually work, but were at a loss as to what else to do for the patient. They agreed to the experimental therapy because the alternative seemed to be certain death. Murray quickly arrived on the ward with his odd-looking machine. It was massive and cumbersome, and took three men to carry it to the bedside. Murray cut into the large femoral vein on the inside of the patient's left thigh. A long, plastic catheter was inserted into it and connected to the dialyser coils. Then Murray cut into the femoral vein in the right thigh, pushing another catheter up into the vessel until it reached the inferior vena cava. Heparin solution (the other vital component for successful dialysis that Murray had himself helped to develop) was then injected into the patient's bloodstream and into the machine. When the machine was switched on and its pump started moving, dark red venous blood was carried into the Cellophane tubing and slowly flowed through the narrow coils in a 15-quart (14 litre) glass jar containing the dialysate, perched on the bedside table. The blood then passed through an air trap that removed any bubbles, and returned to the patient's circulatory system. A thermostat control had been built into the machine to maintain the patient's blood temperature outside the body [22].

It was a case of trial and error. Murray was experimenting with the number and length of treatments. The first treatment was

discontinued after only 1 h when the patient developed a severe chill. Nevertheless, the patient had been revived from the coma. A second treatment was administered 2 days later when the patient slipped back into unconsciousness. After 8 h of treatment from the artificial kidney, the patient was again revived. A third treatment was necessary 3 days later when the patient relapsed. After 6 h of treatment, she was revived once more. This final session on the artificial kidney constituted the breakthrough. The following day, the patient's kidneys began to function and residual uraemic toxins and excess liquid were soon washed out of her body. She made a steady recovery and was released from hospital 33 days after being admitted [23].

Despite its initial success, the artificial kidney machine was used in few cases thereafter—over the next several years up to 1949 no more than 11 patients received treatment. There were several reasons for this. Toronto Hospital medical men viewed the artificial kidney machine—rightly—as still experimental, offering only short-term, intermittent treatment to patients suffering from acute renal failure, and they were reluctant to use the machine as anything but a last-ditch therapy. Also there were no full-time laboratory services or technicians available to support dialysis treatments. The treatments therefore monopolized Murray's and his assistants' time, and for Murray, the artificial kidney was only a secondary line of investigation. He was a surgeon, and he devoted more and more of his time to the new, exciting field of cardiac surgery. Therefore poor promotion and acceptance of this first artificial kidney was due to a lack of support and interest in renal therapy at the Toronto Hospital, and perhaps Murray's own restless nature. The artificial kidney was eventually moved to the hospital basement and seldom used after 1949.

Murray's second artificial kidney machine (1952–53)

By the early 1950s, Murray was director of a privately funded laboratory with full-time research staff. Also by this time, a greater number of commercial and home-made artificial kidney machines were being circulated and used in North American and European hospitals. But these machines remained large and clumsy, and reported clinical series continued to deliver mixed results. The initial success of Murray's first artificial kidney and his new research setting stimulated him to build a second, improved machine. In 1952, Murray initiated work on a second-generation artificial kidney with Dr Walter Roschlau. They intended to offer a more compact and efficient machine to the medical marketplace.

The Murray–Roschlau artificial kidney was an improved model from the original machine with substantial differences . The significant feature of this second-generation machine was its parallel plate design instead of the original vertical coil dialyser,

making it much more compact. Roschlau (who appears to have been unaware of similar designs by Skeggs and Leonards [24] and McNeil [25]) had designed a plate-type dialyser with an enlarged surface area and reduced blood-volume requirements. He experimented with flow patterns, volume requirements, dialysing membrane surfaces, and the production of multiples of blood and dialysate chambers, cannibalizing the original artificial kidney machine for its electric motor, mounting boards, glassware, etc. The fluid storage container was designed to be tucked out of sight under the table, showing `less' machine at the bedside. Its operation was simplified and its efficiency improved; it was easier to handle, clean, and less `frightening'. In 1954, 27 experiments, involving 10 dogs, were conducted to test the performance and reliability of their new machine. Shortly thereafter, this second-generation artificial kidney was used in two clinical cases. Roschlau assembled, sterilized, and transported the machine to the Toronto General Hospital and administered the dialysis treatment. The experimental therapy once again brought successful results. No flaws in the design or function of the machine were noted; however these clinical cases were never reported [26].

Fig.7 The Murray–Roschlau `second-generation' flat-plate dialyser. This was an advanced flat-plate parallel-flow dialyser with 30 layers of dialysis units each with two membranes and two dialysis compartments, forming a dialyser of 0.6 m2 surface area and with a priming volume of only 225 ml.

Conclusion

Murray built and used successfully the first artificial kidney machine in North America. Few medical men outside Toronto were aware of its existence, and Murray himself regarded it as only a secondary line of investigation, losing all interest in the artificial kidney when he lost control over the designs of his machine. Moreover, his machine benefited very few patients.

Inventor of Artificial Kidney

Willem Johan "Pim" Kolff (February 14, 1911 – February 11, 2009) is credited for developing first clinically used artificial kidney machine.

Fig 8. Willem Johan

Kidney dialysis

Kidney dialysis machines represent an excellent example of the life-enhancing synergies that result when chemical engineers join forces with physicians and biomedical researchers. These “artificial kidneys” are essentially mass-transfer devices. They cleanse the blood, removing elevated levels of salts, excess fluids, and metabolic waste products.

The first practical dialysis machine was developed during World War II. Since then many major developments have taken place. One of the major obstacles that had to be overcome, however, was size. To be truly practical a single-patient portable machine was needed.

Fig.9 The first machine used for home hemodialysis, the Milton-Roy Model A, was designed by chemical engineering professor Les Bab in order to help the daughter of a friend. Photo by Jim Curtis. Courtesy Home Dialysis Central.

Bioengineered kidneys

Currently, no viable bioengineered kidneys exist. Although a great deal of research is underway, numerous barriers exist to their creation [27][28][29]

However, manufacturing a membrane that mimics the kidney's ability to filter blood and subsequently excrete toxins while reabsorbing water and salt would allow for a wearable and/or implantable artificial kidney. Developing a membrane using microelectromechanical systems (MEMS) technology is a limiting step in creating an implantable, bioartificial kidney.

The BioMEMS and Renal Nanotechnology Laboratories at the Cleveland Clinic's Lerner Research Institute have focused on advancing membrane technology to develop an implantable or wearable therapy for end-stage renal disease (ESRD). Current dialysis cartridges are too large and require superphysiologic pressures for blood circulation, and pores in current polymer membranes have too broad of a size distribution and irregular features. Manufacturing a silicon, nanoporous membrane with narrow pore size distributions improves the membrane's ability to discriminate between filtered and retained molecules. It also increases hydraulic permeability by allowing the mean pore size to approach the desired cutoff of the membrane. Using a batch-fabrication process allows for strict control over pore size distribution and geometry.[8]

In recent studies, human kidney cells were harvested from donated organs unsuitable for transplantation, and grown on these membranes. The cultured cells covered the membranes and appear to retain features of adult kidney cells. The differentiated growth of renal epithelial cells on MEMS materials suggests that a miniaturized device suitable for implantation may be feasible.

How artificial Kidney works

Artificial kidney works the same manner as the real kidney, in that unwanted substances are removed from blood across a differentially permeable membrane, which allows small molecules(molecular weight up to 300 or 400) to be separated from larger ones. This is known as dialysis. The principle on which the artificial kidney works is therefore simple: the patient's blood must flow on one side of the membrane, or through a tube made of the membrane, with a dialyzing fluid (or dialysate) on the other. Some substances (with small molecules) will diffuse out of the patient's blood into the dialysate and be carried away as waste. The blood cells, protein, and amino acid molecules which are too large to escape will remain in the blood. The differentially

permeable membrane is made of viscose-cellulose (Visking tubing) 0-025 mm thick, and its surface area is 0-9 m2 , about half that of the total filtering area of both kidneys. The artificial kidney simulates the various functions of the kidney in the following ways. 1 Salts and waste products of metabolism will diffuse out of the blood into the dialysate and be carried away. The problem here is not just to remove substances but to prevent the removal of too much. The dialysate is therefore made up from sodium chloride, sodium acetate, potassium chloride, magnesium chloride, and calcium chloride, in aqueous solution, in the same concentra- tion of salts as is present in the plasma of a normal person at a pH of 7-4. Unwanted substances will thus be removed but needed ones kept. In addition, the dialysate contains 1-2 per cent of dextrose to maintain a high osmotic pressure on the outside of the membrane.Ionic exchange between blood and dialysate takes place until equilibrium is reached. Perfect equilibrium may never be achieved, but enough urea, potassium, and sodium are removed to keep the patient well. Unlike the real kidney, the artificial one has no problem of having to reabsorb valuable sub- stances back into the blood. They are retained owing to the composition of the dialysate and the small pores of the Visking tubing. The process of achieving equilibrium is slow and chronic patients have to spend all night, twice a week, connected to the machine. Acute cases are put on to the machine once every few days. Blood which has abnormal salt concentrations at the start of the process of dialysis is normal at the end, the waste products having been removed. 2 The removal of water presents a different problem. It cannot diffuse out of the blood because there is more water in the dialysate than in the blood itself. The problem is solved by partially closing the venous tube with a clip to increase the blood pressure to 200 mmHg (the normal pressure is about 90 mmHg). This causes ultra-filtration in the same way as in the real kidney and some 100-200 cm3 of water are removed per hour. 3 The pH of the blood falls only from 7-4 to about 7-3 between two treatments. This is because the body's store of bicarbonate is utilized to buffer the blood, the bicarbonate being reduced to about 75 per cent of its normal value. The machine therefore maintains pH by replacing the lost bicarbonate. Earlier treatments used to incorporate bicarbonate (as sodium bicarbonate) into the dialysate, but sodium acetate is now used. This diffuses into the blood, and is then metabolized to bicarbonate.

Fig.10 working of artificial kidney The artificial process thus differs from the natural one in two ways: a. reabsorption of some of the materials which pass through the membrane does not take place, and b. there is a continuous flow of water on the outside of the membrane carrying away those materials which have passed through. These, then, are the general principles on which all types of artificial dialysers work. To see how the principles have been translated into workable reality, one must look more closely at one type of machine.

Need for a bioartificial kidney

Over 300,000 Americans are dependent on hemodialysis as treatment for renal failure, but according to data from the 2005 USRDS 452,000 Americans have end-stage renal disease (ESRD).[2] Intriguing investigations from groups in London, Ontario and Toronto, Ontario have suggested that dialysis treatments lasting two to three times as long as, and delivered more frequently than, conventional thrice weekly treatments may be associated with improved clinical outcomes[30] Implementing six-times weekly, all-night dialysis would overwhelm existing resources in most countries. This, as well as scarcity of donor organs for kidney transplantation has prompted research in developing alternative therapies, including the development of a wearable or implantable device.[31]

USES OF ARTIFICIAL KIDNEY

An Artificial Kidney to take Patients off the Transplant Waiting List

Real organs are in short supply, so maybe this mechanical one (made with real human cells!) can help instead.

As anyone who has watched a medical drama knows, organs are in short supply and must be rushed everywhere in coolers, only to be delivered at the last possible moment. This is actually kind of true. In the U.S., 570,000 people suffer from chronic kidney failure, but last year there were only 16,812 kidneys available to be transplanted. A staggering 92,000 patients were left on the waiting list, which can be a death sentence.

There is no substitute for a real kidney, but researchers at UCSF and nine other labs have for years been working on an artificial version that can allow patients to live without dialysis, and without having to take immune suppressing drugs that normally prevent transplanted kidneys from being rejected by the body. This month, the FDA announced that it has selected the artificial kidney project for its Innovation Pathway, a program designed to help breakthrough technologies reach market faster than they might otherwise.

The implantable artificial kidney performs the water-balancing and metabolic functions of the real thing using lab-grown cells and nanofilters that remove blood toxins. No pumps or outside power supplies are needed; the body’s blood pressure pushes along filtration. "It’s a mechanical device combined with cells," explains Dr. Shuvo Roy, the leader of the artificial kidney project.

The device isn’t a perfect replica of a real kidney, but it provides enough functionality that patients can ditch dialysis and have complete freedom of mobility. The device can’t, for example, produce an important kidney chemical, called erythropoietin, which stimulates red blood cell production. Patients using the artificial kidney will have to take a drug for this, just like dialysis patients.

But unlike real transplanted kidneys, which have an average lifespan of 10 to 12 years, the artificial kidney can last indefinitely (new cells may have to be implanted through an injection or small port every two years.)

It’s a mechanical device combined with cells.

The kidney transplant waiting list won’t disappear anytime soon, even with the emergence of the artificial kidney. But the people who get kidneys from the waiting list are often close to death; healthier patients are left waiting. The artificial version

could be an option for patients who are unlikely to get a real transplant.

Roy hopes that a clinical trial can begin in 2016. The device could be on the market by the end of the decade, with a price tag that’s comparable to what it currently costs to maintain a transplant (about $30,000 a year).

"One of the encouraging things for us is that the fundamental scientific basis for the artificial kidney has already been established. We know the concept works. The challenges ahead are mostly engineering challenges," says Roy.[32]

Fig.11 Dr Shuvo Roy at work in lab

New Artificial Kidney a Viable Alternative to Dialysis

Dialysis is only an imperfect solution to kidney failure, as it replicates the kidneys’ waste functions, but cannot carry out any of the kidneys’ endocrine functions. Dialysis also limits mobility and carries with it an infection risk at the dialysis site.

Researchers at UCSF and nine other labs are in the process of creating an artificial kidney that could be used in case a donor organ is not available and as a better alternative to dialysis. The artificial kidney is a combination of real cells and nanofilters, a “mechanical device combined with cells,” describes project lead Dr. Shuvo Roy.

The artificial kidney can last indefinitely, as long as new cells are injected into the kidney every two years or so. Although the artificial kidney can’t produce any of the compounds that a real

kidney can, the artificial kidney gets the job of waste filtering done without any hassle to the patient.

Fig.6 A research team at led by UCSF professor Dr. Shuvo Roy may have found an alternative to kidney dialysis and a solution to kidney shortages in the U.S

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