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These past two weeks, the team has conducted further research for design purposes.

As we learn more about the novel PyKC, we are leaning towards utilizing this design over the mechanical frame. The hydrogel meets our requirements for long-lasting(though degradability research is only available for 1 year), pH survivability, and water insolubility.

The hydrogel design can now be broken down into two more sub designs: stented and non-stented. The stented design would utilize a similar anchoring mechanism as cardiovascular stents. One downfall of this would be the inability to fully dissolve in DMSO, requiring a more invasive removal procedure, one of the reasons the mechanical valve was not selected. The other design would be a simple press-mold into the vesicoureteral junction made up solely of the hydrogel.

The team has been in touch with Dr. Debapratim Das of the Indian Institute of Technology for assistance in our utilization of the hydrogel. He has provided further information to answer our questions when needed, and has offered to provide the protein peptide base to make the hydrogel.

Additionally, the team has performed hazard analysis on foreseeable risks associated with the valve and delivery system. Hazard analysis is used to grade risk based on severity and occurrence. Additionally, we have included mitigation, or preventative measures, for risks assigned a risk representation of “R2.”

These two weeks, the team has focused on initial design.

Our first idea for the valve is to use PyKC, a novel hydrogel. This hydrogel is insoluble in water and biological fluids. DMSO, frequently used for bladder flushing, could be used to degrade PyKC, making for a simple removal process when the device is no longer needed. As this is a novel material, more information is needed to finalize decisions going forward.

Our Second idea is to utilize a metal frame with a coating and a mesh within. The frame would be designed to have a ring of hollow tubes allowing it to expand and contract as needed. It would also be coated in a layer such as silicon dioxide to prevent cell growth.

For the catheter, we are planning to utilize a delivery mechanism similar to the procedure to implant ureteral stents. Via cytoscope, a guidewire is inserted into the urethra, through the bladder, and up the ureter. Once in position, the stent is fed along this wire with a catheter “pusher,” until the stent is in the proper position. At this point the guidewire and pusher are removed, leaving the stent behind.

Additionally, the team has set up an initial budget and gaant chart to follow. Subject to change.

Budget

Gantt Chart – This is the schedule we anticipate to follow for the remaining duration of this project.

This week, the team has focused on design standards to follow. Standards, developed by experts in their field, are rules, testing methods, definitions, recommended practices, or specifications that promote uniformity. Below are the standards that will be referenced in the design and testing of this project. Subject to change.

Standard	Name	Justification
ASTM F1635-16	Standard Test Method for in vitro Degradation Testing of Hydrolytically Degradable Polymer Resins and Fabricated forms of Surgical Implants	This standard will be referenced in the consideration of different materials that could be used as the material for the valve, if a biodegradable material is the option chosen.
UNE – EN 13868-2002	Test Methods for Kinking of SIngle Lumen Catheters and Medical Tubing	This standard will be referenced in the testing of the polymer and how the effects of different pH values change it’s properties due to degradation.
D3826-18	Standard Practice for Determining Degradation End Point in Degradable Polyethylene and Polypropylene Using a Tensile Test	This standard will be referenced in both the catheter and valve design. The standards for leakage and surface properties will be utilized, in addition to the testing parameters for leakage, pressure under standard conditions, and the determination of flow rate through the valve. Though the catheter will be a short-term implantation into the body, the valve should follow the constraints of a normal catheter for long-term placement in the body.
ISO 10555-1ASTM F2004-05	Intravascular Catheters Sterile and Single-Use Catheters	These standards will be referenced in designing the valve. The material that will be used to design the device has not been chosen but there is a possibility of using an alloy. These two standards provide procedures that determine the transformation temperatures of nickel-titanium shape memory alloys.
ASTM F2082-06	Standard Test Method for Transformation Temperature of Nickel-Titanium Alloys by Thermal Analysis
ASTM G71-81	Standard Guide for Conducting and Evaluating Galvanic Corrosion Tests in Electrolytes	This standard will be referenced in the valve design. Since a material has not been picked yet, it is possible that a metal or a polymer and a metal combination will be used, making this standard necessary for testing. This standard covers corrosion tests when in contact with electrolytes under low flow conditions, and will likely have to be modified to be used for the valve design.
FDA Code of Federal Regulations Part 876.513	Urological catheter and accessories	This code will be referenced with respect to the catheter, as this code discusses catheters used in the urethra. It also discusses how the catheter is classified, based on some requirements.

So far, the team has been discussing and finalizing requirements. Since this project consists of two main devices, an implantable valve and a catheter delivery mechanism, requirements were broken down as such and are as follows:

Valve Requirements

Requirement	Specification	Justification
1.) The device must remain intact while it is serving its purpose in the patient’s body.	1.1) Must be able to support a large range of pH present in urine (pH 5-8)  [5].	1.1) pH changes can damage a material
	1.2) Last at least 5 years [8]	1.2) In children, VUR often fixed within 5 years [8]
2.)  The device must support normal urine flow into the bladder	2.1) The device must be able to support flow rates up to 25 mL/hour	2.1a) Flow rate is between 17.5-23.6 mL/hour [12]
		2.1b) Urine flow is pulsatile/dynamic flow, not just steady state [12].
	2.2) The device must be able to support intra-abdominal pressure up to 20 mmHg	2.2) Intra-abdominal pressure  up to 5 mmHg is normal in adults, but with conditions such as obesity, it can get as high as 15 mmHg. Above 20 mmHg is associated with organ dysfunction [14].
3.) The device must “grow” with a child if a long-term fixture	3.1) The material needs to be able to elastically strain 233%  to change with the ureter.	3.1) The ureter starts at 3-5 mm in healthy kids, greater than 7 mm in kids with VUR [15]
4.) The device must be biocompatible		4.) For any medical device approved by the FDA, biocompatibility testing must be doe following ISO 10993-1 [1].
5.) The device must stay in place		5.) Movement of the valve will initiate an immune response [4]

Catheter Requirements

Requirement	Specification	Justification
1.) The device must be able to reach the vesicoureteral junction.	1.1) The placement device must be able to range in length from 2 cm to 30 cm to accommodate both males and females, children and adults.	1.1a) The adult male urethra ranges from 15-30 cm long [2].
	1.1b) The average female child’s urethra length is 2.59 cm [3]
2.)The device must be able to fit into the urethra.	2.1) The catheter tubing must be less than 3 mm in diameter.	2.1) In children, the average diameter of the urethra is 3-4 mm [9].
3.1) The device must be able to place the valve correctly, and then be separated from the valve for removal from the body.	3.1) Once placed, the valve does not move more than 2 mm once separated from the catheter.	3.1a) This is the function of the device, as a catheter long-term would be uncomfortable for a child.
	3.1b) If the valve moves during placement, it needs to be close enough to still support the natural flap.
4.) The device must be biocompatible.		4.) For any medical device approved by the FDA, biocompatibility testing must be doe following ISO 10993-1 [1].

Additional Requirements

Requirement	Justification
1.) The delivery of the devices must be simple and does not require additional surgical training.	1.) The goal of the company is to make the device usable internationally, especially in areas with fewer medical professionals.
2.) The cost of the procedure must be equivalent of already existing treatments	2.) The goal of the company is to ensure that insurance companies cover most of the cost.
3.) The devices must be manufactured at TCNJ	3.) Rules of senior project
4.) The devices must be as environmentally friendly as possible	4.) The goal of the company is to ensure a low carbon footprint, which can be done through the use of recycled materials in packaging

 

References

[1] FDA, Special Considerations – Biocompatibility. 05/22/2020. https://www.fda.gov/medical-devices/premarket-notification-510k/special-considerations#bio

[2]Kohler, Tobias S et al. “The length of the male urethra.” International braz j urol : official journal of the Brazilian Society of Urology vol. 34,4 (2008): 451-4; discussion 455-6. doi:10.1590/s1677-55382008000400007

[3]Halleran, Devin R., et al. “Urethral Length in Female Infants and Its Relevance in the Repair of Cloaca.” Journal of Pediatric Surgery, vol. 54, no. 2, 2019, pp. 303–306., doi:10.1016/j.jpedsurg.2018.10.094.

[4] “Recommendations.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 5 Nov. 2015, www.cdc.gov/infectioncontrol/guidelines/cauti/recommendations.html.

[5] Feher, Joseph. Quantitative Human Physiology. Elsevier. 2nd Edition. 2011

[6] Burr, RG and Nuseibeh IM. Urinary catheter blockage depends on urine pH, calcium, and rate of flow. Spinal Cord. 35: 521-525. 1997. https://www.nature.com/articles/3100424

[7] Gopferich A. Mechanisms of polymer degradation and erosion. Biomaterials. 17(2): 103-114. 1996. https://www.sciencedirect.com/science/article/pii/0142961296857553

[8] (https://www.hopkinsmedicine.org/health/conditions-and-diseases/vesicoureteral-refluxvur#:~:text=Most%20children%20who%20have%20grade,Surgical%20treatment%20is%20also%20available.)

[9] Chow, Jeanne S., and Annemieke S. Littooij. “Urogenital Pathologies in Children Revisited.” SpringerLink, Springer, Cham, 1 Jan. 1970, link.springer.com/chapter/10.1007/978-3-319-75019-4_7.

[10] Kakizaki H;Moriya K;Ameda K;Shibata T;Tanaka H;Koyanagi T; “Diameter of the External Urethral Sphincter as a Predictor of Detrusor-Sphincter Incoordination in Children: Comparative Study of Voiding Cystourethrography.” The Journal of Urology, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/12544337/.

[11] B;, Reinking LN;Schmidt-Nielsen. “Peristaltic Flow of Urine in the Renal Capillary Collecting Ducts of Hamsters.” Kidney International, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/7300113/.

[12] Kim, Kyung-Wuk, et al. “Analysis of Urine Flow in Three Different Ureter Models.” Computational and Mathematical Methods in Medicine, Hindawi, 4 June 2017, www.hindawi.com/journals/cmmm/2017/5172641/.

[13] Rollino, Cristiana, et al. “Vesicoureteral Reflux in Adults.” Giornale Italiano Di Nefrologia : Organo Ufficiale Della Societa Italiana Di Nefrologia, U.S. National Library of Medicine, 2011, www.ncbi.nlm.nih.gov/pubmed/22167611.

[14] Milanesi, Rafaela, and Rita Catalina Aquino Caregnato. “Intra-Abdominal Pressure: an Integrative Review.” Einstein (Sao Paulo, Brazil), Instituto Israelita De Ensino e Pesquisa Albert Einstein, 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC5234758/.

[15] “Megaureter & Ureter.” Cleveland Clinic, my.clevelandclinic.org/health/diseases/16305-megaureter.

Vesiscoureteral reflux(VUR) is the condition where urine flows backwards from the bladder into the ureters. It is typically diagnosed in young children, but can affect people through adulthood. Though sometimes the condition corrects itself as the ureters grow, a side effect of VUR is the frequent development of urinary tract infections, which, when untreated, can lead to kidney damage.

There are two types of VUR, primary and secondary. Primary VUR is caused when there is an anatomical defect in the junction between the bladder and the ureters, which does not prevent backflow properly. The secondary VUR is due to the bladder filling up too much, either due to blockages or failure of the bladder muscle and nerves. Both are graded on a 1-5 level scale, with 5 being the most severe. The severity is graded on how far the backflow of urine flows up the ureters. Severe complications of kidney damage due to VUR include failure, scarring, and high blood pressure.

Existing treatments aim at the prevention of UTIs and kidney damage, with both surgical and managerial options. *Managerial treatment relies on antibiotic treatment of UTIs, which can lead to antibiotic resistance over time. Surgical repair is typically for higher grades of the condition and includes endoscopic, laproscopic, and open techniques, requiring hospital stays. Typically children with severe grades of VUR have pre-existing conditions which make surgical risks higher, so there is a need for a less invasive procedure to correct high-grade VUR.