Significance: - Pitt



LEC Biopsy Tool SBIR Application

Investigators: Kevin Mihelc, Amine Hallab, Jen Bacior, Hiroki Meguro

Submittal Date: April 29, 2005

A. Specific Aims

Liver biopsy is a common procedure used to diagnose abnormal liver conditions. Current methods for the procedure include percutaneous biopsy, performed through the host’s skin, and invasive biopsy, performed during open liver exposure. Invasive biopsies are routinely executed for liver transplants and animal research studies.

The goal of this project is to design a multi-functional invasive instrument, the Liver Excision-Cauterization (LEC) Biopsy Tool, that will allow simple acquisition of a liver biopsy while immediately cauterizing the host liver to seal the incision wounds. Additionally, the LEC device will be compatible with existing hospital bovie systems. The tool will be capable of cauterizing the host liver in both a rapid and an efficient manner in order to prevent excessive blood loss from the wound. The LEC device will also be designed to allow for quick biopsy insertion into liquid nitrogen before tissue metabolic processes cease; a common technique applied clinically. In cases of extracting liver tissue where spot probe freezing has occurred, the tool will be able to maintain the biopsy’s temperature and protect it from gaining heat during the cauterization process.

The design of the LEC biopsy tool will prevent against user electrical shock and burn from exposure to the bovie electrical current, and testing will prove that adequate safeguards have been employed. Effective sterilization efforts will also be investigated in order to avoid infection of the wound and contamination of the biopsy and tool. The requirements of efficient cauterization and simple biopsy removal will also be evaluated through the testing regimen.

• Specific Aim 1: Design an invasive device to be used for liver biopsy extraction.

• Specific Aim 2: Fabricate the device for prototype testing.

• Specific Aim 3: Test Phase I device using an animal model to establish basic

functionality.

B. Significance

Over twenty-five million people are or have been afflicted with a liver disease in America1. Researchers have identified more than 100 different acute and chronic liver diseases1. Liver disease can persist for decades without causing overt evidence of serious liver damage2 and without an adequate way of testing for diagnostic and staging purposes, liver disease can go unchecked and lead to massive health problems later in life. It is due to this prevalence in the population that liver research appropriations totaled $261.7 million in 2001, alone, and are rapidly increasing1.

Liver biopsy is an essential tool in hepatology. It can be used to make diagnoses, determine staging, and assess prognosis in patients who show signs of liver disease. It has proven valuable in several different applicational contexts, such as determining presence and staging of Hepatitis C, alcohol-induced liver disease, Hepatitis B, Genetic Hemochromatosis, cholestatic liver diseases, and Autoimmune Hepatitis in liver patients3. It is also an invaluable means to assess progress in liver transplantees3.

Invasive liver biopsies, or liver biopsies that are performed during open liver surgery, are of specific importance in both the research and clinical context. The use of liver biopsy in those with normal liver tests following liver transplantation may reveal unexpected abnormalities requiring intervention4 and, in the research context, invasive liver biopsies have provided priceless information regarding disease progression and drug development4.

Currently, these invasive liver biopsies are performed using standard surgical scissors, a Bovie Electrosurgical Generator and a Bovie Disposable Electrode. A surgeon or researcher cuts a wedge-shaped piece of the liver in question using the scissors. After this, he must rush to use the bovie and electrode to cauterize the wound to the liver before substantial blood loss occurs. Even when the surgeon is fast, this cauterization still takes two to three minutes because it is happening at a point-by-point level. This means that he must touch the electrode to individual points on the biopsied liver to cauterize the wound. This is not only time-consuming, it could potentially cause problems in the operating room or research lab because of its lack of efficiency. In addition, for metabolic studies, the liver biopsy must first be frozen with liquid nitrogen, via pre-biopsy spot-probe freezing and post-biopsy immersion in order to preserve for analysis the state of the metabolic processes that were taking place at the time of biopsy.

There is an increasing need for a biopsy tool that could safely and effectively cut a properly shaped biopsy, cauterize a biopsy wound, protect the biopsy from drastic temperature changes during cauterization, and allow for quick removal of the biopsy from the liver.

Previous research indicates that flat-plate conductivity is effective based on the availability of the large surface area across the plate for electrical and thermal conduction5. This research indicates that it is, indeed, possible to conduct the current from a bovie in such a manner as to incite large surface area cauterization of a wound. In addition, the mechanical and electrical properties of stainless steel suggest that it is the most cost-effective material to use, due to its vast capabilities in conduction—both electrical and thermal6.

Ceramics have been extensively tested as coatings to protect metallic and silicon-based components in multiple devices. One study investigated the effects of ceramic thermal barrier coatings on components in gas turbine engines and found that these coatings adequately protect against extreme changes in temperature7. These findings suggest that ceramic will be an adequate material to properly insulate and protect the excised biopsy.

The purpose of our design is to achieve excision, cauterization, and thermal protection in a single tool. Our excision method will only require one cut, instead of two; our cauterization method will be flat-plate cauterization using stainless steel allowing for ease of use and efficiency; and our thermal protection of a ceramic insulator will allow for alleviation of the scramble to transfer the biopsy to the liquid nitrogen, post-excision. We intend for our solution to be a low-cost, efficacious, and efficient alternative to the current method of invasive liver biopsy acquisition.

C. Relevant Experience

The design team consists of four students who bring a diverse set of skills to the project. Amine Hallab, Jen Bacior, Kevin Mihelc, and Hiroki Meguro are all undergraduate students majoring in bioengineering. They are being aided in the development of this project by Dr. Dympna Kelly, M.D. and Dr. John Patzer, Ph.D.

Amine Hallab is in the Biotechnology and Artificial Organs concentration and his coursework includes a minor in Mathematics. He is an assistant researcher in Dr. Patzer’s lab, working on artificial liver support systems and bound solute dialysis. Additionally, he is a TA for freshman-level math courses at the University. His expected graduation date is the spring of 2005.

Jen Bacior’s concentration is Biotechnology and Artificial Organs, and she is also getting a certificate in Conceptual Foundations of Medicine. She is employed as a clinical technician on extracorporeal membrane oxygenation (ECMO) at Children’s Hospital. She has worked with SolidWorks and CAD modeling, and has C++, HTML, Matlab, and some JAVA programming experience. She expects to graduate in December of 2005.

Kevin Mihelc is in the Biotechnology and Artificial Organs concentration. He works as a lab manager in the Aerosol Lab at the Pulmonary Annex of the UPMC Bronchoscopy Lab at Montefiore Hospital. He is fluent in programming in the C and Matlab programming languages and has done some programming in C++, Matlab Simulink, SolidWorks, COSMOSWorks and COSMOSFloWorks as well. He is also familiar with FDA regulations and quality systems management. He expects to graduate in the spring of 2005.

Hiroki Meguro is also in the Biotechnology and Artificial Organs concentration. His research focuses on investigating a rotary ventricular assist device (VAD) called the Heartmate II, specifically thrombus formation in rotary pumps. He is in his third semester of VAD research in Dr. William Wagner’s Thrombosis Lab. He has experience programming with SolidWorks, FloWorks, Matlab and HTML. His expected graduation date is December of 2005.

Dr. Dympna Kelly is a transplant surgeon at UPMC. She is involved in research focusing on increasing the success rate of partial liver transplants and is also the recipient of the American Liver Foundation Liver Scholar Award 2003.

Dr. John Patzer is the Coordinator of the Bioartificial Liver Program in his appointment in the Department of Surgery at the Thomas E. Starzl Transplantation Institute. He is also involved in the evaluation of metabolic artificial organs. In addition, he has an appointment in the Department of Chemical and Petroleum Engineering.

D. Experimental Design and Methods

In order to assure the efficiency of the LEC biopsy tool, the functions must be defined and the methods of testing must be analyzed. The design procedures of the LEC biopsy tool have been divided into three separate components and each of the three further divided into sub-components.

1. Mechanism of achievement of LEC functions

1. Design and materials

2. Excision

3. Temperature control

4. Cauterization

2. Prototype Fabrication

2.1 Advantages of SLA

3. LEC prototype functionality testing

3.1 COSMOSworks testing

3.2 Testing of tissue excision and cauterization

3.3 Testing of thermal and electrical insulation of biopsy sample

3.4 LEC user assessments

Specific Aim 1: Design an invasive device to be used for liver biopsy extraction.

D.1 Mechanism of Achievement of LEC functions

The design of LEC biopsy tool is only valid for surgical biopsies. Surgical biopsies are consistently required for liver research studies and liver transplants. The primary, ongoing aim of the liver research studies is for the characterization of foundation of metabolic processes. Metabolic processes require an immediate freezing of the excised liver tissue because the metabolites being measured can be affected by the time from excision to freezing8. The prior procedure of our technique required a freezing probe to freeze the desired area of tissue prior to excision. The frozen area of tissue will then be excised. During excision, the bleeding sides of the liver will be cauterized by LEC flat-plate conductance in conjunction with the bovie. The freezing temperature of the biopsy will be kept constant by the use of reliable insulation.

D.1.1 Design and Materials

The device-user interface of the LEC tool will resemble the handles on a pair of standard surgical scissors. The handles and shaft of the tool will be made of conducting stainless steel of grade 316/L/H.

The section of the LEC that performs the majority of the required design functions will be constructed as two halves of a volumetric triangle. The outer layer of the triangle will be made of the conducting stainless steel of grade 316/L/H. The inner layer will be made of a sharpened ceramic. The handles, the body, and the rest of the tool will be made from stainless steel. Figure 1 presents a secure estimate of the LEC future design.

[pic]

The sharp boundaries were chosen to be ceramic so that at a complete cut, a complete layer of insulation will encounter the tissue biopsy. Ceramic has a low magnitude of thermal conductivity, which will provide the biopsy with the desired thermal protection. The low resistivity of the stainless steel will allow electrical current to flow through the handles to the outer layer of the volumetric triangle, while the high resistivity of the ceramic will adequately protect the biopsy from the current. This means that the wound will be cauterized by the current flowing through the LEC tool, but the biopsy will remain uncauterized, as per the original client specifications. Table 1 presents the required parameters of the ceramic and the stainless steel for heat transfer analysis.

|Material |Density |Specific Heat |Thermal Conductivity |Electrical |Compressive Strength |

| |(g/cm-3) |(J/kg- K) |(W/m-k) |Resistivity |(MPa) |

| | | | |(Ω-cm) | |

|Ceramic |2.52 |790 |1.46 @ 25˚C |>1016 |345 |

|Stainless Steel |8.03 |485 |14.6 @ 100˚C |7.40 x 10-6 |~200-300 |

|316/L/H | | | | | |

Table 1: Materials properties of the ceramic9 and stainless steel10.

D.1.2 Excision

The mechanism of excision will be a simple operation, the same as operating a pair of scissors. The major requirement of LEC excision function is to obtain sharp edges on the boundary of the triangles. Dullness of the blades may result in tissue damage or a shredded cut of the liver tissue, which, in turn, will complicate the cauterization process.

D.1.3 Temperature Control

Post-excision, the liver biopsy will physically be insulated inside the triangles of excision. Thermal insulation of the biopsy will also be achieved by ceramic layers on the inner volume surface of the triangles as shown in figure 1. In order to assure the thermal insulation, the temperature of the frozen biopsy was calculated after time, t, using Equation 1, where T is used to denote temperature, [pic] denotes density, c denotes specific heat, and K denotes thermal conductivity. Note that there is a heat generation parameter in function of position and time, this will be considered in thermal energy balance analysis and results shown in the appendix The amount of heat gained by the tissue has been theoretically found to be insignificant, with the boundary temperatures as high as 90˚C; however, further calculations will be presented in the heat transfer domain. Matlab’s Simulink software will be also used to determine the behavior of heat transfer rate with respect to time. The dimensions in Figure 1 may be subjected to variation, thus the level of accuracy will be maximized as a minimum amount of time for a successful cauterization.

Equation 1: Used to calculate the theoretical temperature of the biopsy within the LEC.

D.1.4 Cauterization

Immediately after the time of complete excision, the bovie will be put into contact with the handles of the LEC. This process will allow a high magnitude of electrical current to pass through the conducting body of LEC to the outer layers of the triangles in order to generate a cauterization temperature of 80˚C11. The excised blood vessels of the liver will then be cauterized and an immediate discontinuation of bleeding will be achieved. The generated high temperature will not have an effect on the tissue biopsy’s temperature. The thickness of the ceramic insulation was determined to thermally and electrically protect the frozen tissue of liver.

Thermal unsteady state analysis is presented in Appendix A in a power point format.

Specific Aim 2: Fabricate a prototype for Phase I in vitro testing.

D.2 Prototype Fabrication

The LEC Biopsy Tool was rapid prototyped by QuickParts, an online manufacturing services company, via Armor-Plated Stereolithography (SLA). This method involves using an ultraviolet laser to trace the part in a vat of photo-curable liquid resin polymer (Somos 14120 ABS-like plastic), one layer of thickness (0.20”) at a time. Once the model is completed in this vein, it is placed in an ultra-violet light oven for final curing. After this curing, the part is painted with a conductive paint and a coating of copper is applied using an electroplating process. After the copper has formed an adequate base coat of conductive material, a coating of Nickel is applied via a second round of electroplating. This second round of electroplating completes the process and leaves a solid plastic part that has a 3-mm thick layer of conductive material coating the outside.

D.2.1 Advantages of SLA

The reasons for using this process to develop the LEC Biopsy prototype are two-fold in nature. The first reason being that, using this process and this vendor, the LEC was created in a period of approximately a week. The second, more important reason justifying the use of QuickParts’ Armor-Plated SLA process is that this process not only creates a prototype that meets our needs for conduction, but it also increases the strength and stiffness of the prototype. Additionally, the Nickel coating makes the part virtually waterproof, which acts as a safety in sterilization because there is no danger that the tool would absorb fluids from the liver it is being used to take a biopsy from.

Specific Aim 3: Test the Phase I device using an animal model to establish basic functionality.

D.3 LEC Prototype Functionality Testing

To ensure proper functionality of the LEC Biopsy tool, the prototype was subjected to a preliminary and mechanical testing regimen. Preliminary testing was conducted using COSMOSworks to investigate heat transfer through the insulator into the biopsy tissue. The outcome of this testing resulted in approval to build a physical prototype with acceptable specifications. This prototype was then subjected to several mechanical tests to certify proper functionality. The model for mechanical testing was a deceased porcine liver. The pig had passed approximately 20 minutes before actual testing began. To access the liver, a long incision was made in the stomach cavity of the pig. Testing proceeded until device performance could be accurately assessed. The procedure was performed under the guidance of animal research physicians. In the event of unsatisfactory results, the prototype will be altered and redesigned. The modified prototype will then proceed through the same testing procedure.

D.3.1 COSMOSworks Testing

The preliminary testing of the LEC Biopsy Tool took place prior to the actual prototype order so that it could be determined whether the prototype and proposed final materials would adequately meet the temperature control needs of the desired product specified by the customer. A thermal study was developed in COSMOSWorks in which the materials properties of a porcine liver were applied to a simulated solid within a simulated shell mirroring the insulative interior and conductive exterior of the LEC Biopsy Tool. The materials properties of both the prototype materials (Somos 14120 ABS-Like polymer and Nickel) and the final product (Stainless Steel and Ceramic Porcelain) were applied to the simulated parts of the shell. Then a temperature of 110°C was applied to the back face of the shell and a temperature of -60°C was applied to the simulated liver tissue (Appendix B, Figure 1). Finally, a thermal study was run on each set of materials—the prototype and the final materials—in turn.

The temperature distribution achieved via this process can be seen in Appendix B, Figures 2 and 3. These figures indicate that both the prototype materials and the proposed final product materials will sufficiently meet the temperature control needs of the final LEC Biopsy product, because the temperature of the sample is maintained while the exterior of the shell .

D.3.2 Testing of Tissue Excision and Cauterization

The porcine testing protocol began by examining the cutting capability of the device. Three tests were conducted to observe if a biopsy could be removed from the liver by using the device’s blades for excision. The biopsies were taken from the outer edge of the liver similar to the clinical approach commonly used. Two out of three tests produced a liver sample. These samples, however, were not obtained by a simple, clean cut. The blades either had to be opened and closed a second time, and/or the sample had to be pulled from the host tissue in order to fully remove the biopsy. This outcome demonstrated a need for a modification in the cutting mechanism.

Three different tests were utilized in order to assess the cauterization ability of the LEC tool. Normal bovie settings were used and were established by the research physicians. Simple bovie current conduction was assessed by placing the bottom edge of the top blade onto the liver tissue. The bovie was then contacted. It was observed that the liver tissue turned a brownish color indicating cauterization. Secondly, the technique of both simultaneously cutting a biopsy and cauterizing the wound site was performed. A site at the outer edge of the liver was chosen. While cutting the tissue, the bovie was contacted to the blades. Again, cauterization of the tissue was observed. The biopsy sample was removed after a minute in time. This unsatisfactory time duration can be attributed to the cutting mechanism. In a third test, the tool was placed into an existing biopsy wound site. A liver wedge was first removed from the tissue via surgical scissors. The device was then placed into the site so that the outer walls of the blades were in contact with the walls of the liver site. The bovie again was touched to the blades. Cauterization of the site occurred in 25 seconds of bovie contact. It was necessary for an additional 20 seconds to achieve complete hemostasis as there was a complication in cauterizing the site located at the apex of the triangular blades. The results of these tests meet our expectations for the ability of the tool to cauterize the tissue. With slight modifications to the apex of the conducting blade, and to the outer walls of the conducting blade to promote greater host tissue contact, complete hemostasis of the wound site can be performed within a projected time frame of 15 to 25 seconds depending on the tissue wound size.

D.3.3 Testing of Thermal and Electrical Insulation of Biopsy Sample

Following the cauterization assessment, the tool was tested to demonstrate its ability to protect liver biopsies from the electrical current and heat produced by the bovie system. Two tests were performed in the following manner. A small tissue sample was removed from the liver and placed within the lower blade. The bovie was contacted to the blade for a 60 second time duration. The tissue was then removed and qualitatively examined for tissue burns indicating insufficient insulation. Burns were established as brownish tissue discoloration in comparison to the dark burgundy color of the healthy porcine liver tissue. These tests resulted in the conclusion that the tool sufficiently protected against bovie heat and current generation since both samples were removed with no indication of biopsy damage.

D.3.4 LEC User Assessments

The research physicians were verbally surveyed by our testing team to gain input on the overall concept and design of the LEC device. The consensus of the animal researchers indicated that the tool would be of assistance in obtaining biopsies. The ability of the tool to cut, cauterize, and protect a biopsy sample combines their current technique into one device which simplifies the process. The researchers were very eager for a Phase II device with the specified modifications to enhance performance.

In addition to the modifications listed previously, other user comments included utilizing a bi-polar conduction technique in the tool, adding added user protection from the bovie, and decreasing the size of the finger holes on the tool for increased comfort. The bi-polar method would allow our tool to be connected directly to the bovie system. When the blades were closed by cutting through the liver, an internal circuit in the tool would be completed allowing the bovie current to generate in the blades and promote cauterization. This would eliminate the need to contact the blades with a bovie tip. For added protection, the LEC handles will be dipped into latex or a rubber coating will be incorporated to add a second safe-guard against electrical shock. This adds to the current single protective measure of the surgeon gloves. Finally, the finger holes will be decreased for better user hand comfort.

Works Cited

1. American Liver Foundation. “ALF 2001 Annual Report”. Online. Available: .

2. Diehl AM. “Liver disease in alcohol abusers: clinical perspective”. Alcohol, 2002 May; 27 (1): 7-11.

3. Cadranel JF, Rufat P, Degos F. “Practices of Liver Biopsy in France: Results of a Prospective Nationwide Survey”. Hepatology, 2000 Sep; 32 (3): 477-481.

4. Grant A, Neuberger J. “Guidelines on the use of liver biopsy in clinical practice. British Society of Gastroenterology”. Gut, 2000 Sep; 47 (3): IV1-IV11.

5. Bauer CA, Wirtz RA. “Thermal characteristics of a compact, passive thermal energy storage device”. 2000 ASME IMECE, 2000 Nov.

6. Bogaard RH, Desai PD, Li HH, Ho CY. “Thermophysical properties of stainless steels”. Thermochimica Acta, 1993 May; 218: 373-393.

7. Zhu D, Bansal NP, Lee KN, Miller RA. “Thermal conductivity of ceramic thermal barrier and environmental barrier coating materials”.

8. Belanger MP, Askin N, Wittnich C. “Multiple in vivo liver biopsies using a freeze-clamping technique”. 2002 Mar; 15 (2):109-12.

9. “Macor Machinable Glass Ceramic Thermal Properties”. Online. Available: .

10. “316L Stainless Steel – Allegheny Ludlum – 316L Stainless with high corrosion resistant properties”. Online. Available: .

11. Patel VP, Leveille RJ, Hoey MF, et al. “Radiofrequency ablation of rabbit kidney using liquid electrode: acute and chronic observations”. J Endourol, 2000; 14:155-159

Appendix A

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The model shown above is used for the Femlab simulation below.

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Temperature distribution vs. position over 1 second period.

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As a more applicable model, the temperature distribution was plotted over 100 seconds which is the actual time expected for cauterization.

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The temperature profile is shown above at 0,10,40,80 seconds. The profile will not reach a linear profile since the heat generation is producing 80 C at all times.

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The plot above indicates the validity for our mathematical model where the temperature reaches equilibrium as time approaches infinity. The temperature is distributed over the ceramic when there is generation over 18 minutes.

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Appendix B

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Figure 1: Application of temperature as done on the simulated materials in the COSMOSWorks thermal study. A temperature of 110°C was applied to the back face of the shell and a temperature of -60°C was applied uniformly to the simulated biopsy tissue.

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Figure 2: Temperature distribution after the thermal study was done in COSMOSWorks on the prototype materials, Somos 14120 ABS-Like plastic and Nickel. The scale runs from 110°C at the red end to -60°C at the blue end.

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Figure 3: Temperature distribution after the thermal study was done in COSMOSWorks on the proposed final materials, Stainless Steel and Ceramic Porcelain. The scale is the same as in Figure 2, running from 110°C at the red end to -60°C at the blue end.

-----------------------

t2

t1

L

±

Stainless

Steel layer

Ceramic layer

± = 60Ú[?]

L = 2 cm

t1 = 1.5 mm

t2 = 2.5mm

Figure 1: The image on the left presents a SolidWorks α

Stainless

Steel layer

Ceramic layer

α = 60˚

L = 2 cm

t1 = 1.5 mm

t2 = 2.5mm

Figure 1: The image on the left presents a SolidWorks model of the LEC upper blades. The image on the right presents the dimensions of the LEC triangle of excision where α is the angel between the triangle segments, L is the length of each segment, t1 is the thickness of the stainless steel layer, and t2 is the thickness of the ceramic layer.

Time = 10,000 seconds

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