An allograft bioengineered conduit device for urinary diversion and methods of implantation

Abstract

Bladder cancer primarily affects older adults, with radical surgery often leading to significant complications due to the use of bowel tissue for bladder reconstruction. Provided herein is a new approach using cryopreserved tissue from cadaveric vessels that avoids these complications. This new method makes surgery safer and recovery quicker, reducing hospital stays and improving patients' quality-of-life. This disclosed method is a major advancement in treating muscle-invasive bladder cancer, offering minimal side effects and a faster return to normal life.

Description

Attorney Docket No. 103362-037WO1AN ALLOGRAFT BIOENGINEERED CONDUIT DEVICE FOR URINARY DIVERSION AND METHODS OF IMPLANTATIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 695,993, filed September 18, 2024, the entire contents of which are incorporated herein by reference.BACKGROUND

[0002] Bladder cancer ranks as the sixth most common cancer in the United States and the ninth globally. It predominantly affects individuals aged 70 years or older, with approximately 600,000 new cases diagnosed worldwide annually. Standard-of-care management of muscle-invasive bladder cancer (MIBC) includes radical cystectomy with pelvic lymphadenectomy and urinary diversion, which involves complete removal of the urinary bladder and construction of a “urinary conduit” using a segment of bowel. This conduit has ureteral attachments on one end and is connected to the skin on the other.

[0003] Despite advances in management of MIBC, this surgery is still associated with a high 90-day complication rate (>50%), with most complications arising from the use of bowel segments. [Katsimperis, Stamatios et al. “Complications After Radical Cystectomy: A Systematic Review and Meta-analysis of Randomized Controlled Trials with a Metaregression Analysis.” European urology focus vol. 9,6 (2023):920-929. doi: 10.1016 / j.euf.2023.05.002] Using bowel segments for urinary diversion also has longterm metabolic and infectious complications which can cause significant decrease in quality - of-life (QoL) in an already co-morbid geriatric population. The primary function of the bowel is to absorb nutrients and secrete mucus. Both these properties do not align with proper functioning of the urinary tract and patients have a myriad range of long- and short-term complications associated with ileum. [Anderson CB, McKiernan JM. Surgical Complications of Urinary Diversion. Urol Clin North Am. Feb 2018;45(l):79-90. doi: 10.1016 / j.ucl.2017.09.008]Attorney Docket No. 103362-037WO1

[0004] Therefore, a need exists for an alternative treatment for muscle-invasive bladder cancer (MIBC) that improves the care of cystectomy patients and ensures fewer intestinal, metabolic, and infectious complications.SUMMARY

[0005] According to one implementation, a method of implanting a vascular graft at ureteral procedure site is provided. The method includes providing a vascular graft including a Y-shaped body including a first conduit terminating at a first end, a second conduit terminating at a second end, and a third conduit terminating at a third end. Each of the first conduit, the second conduit, and the third conduit are in fluid communication with each other. The method further includes coupling the first end of the Y-shaped body to a first ureter of the ureteral procedure site such that the first conduit is in fluid communication with the first ureter. The method further includes coupling the third end of the Y-shaped body to a stoma defined through a body wall of a body such that the third conduit is in fluid communication with an exterior of the body.

[0006] In some implementations, the method further includes coupling the second end of the Y-shaped body to a second ureter of the ureteral procedure site such that the second conduit is in fluid communication with the second ureter.

[0007] In some implementations, the first and second ureters are in fluid communication with the stoma, bypassing a urinary bladder of the ureteral procedure site. In some implementations, the vascular graft provides for urinary diversion.

[0008] In some implementations, the first end of the Y-shaped body is coupled to the first ureter via one or more stiches. In some implementations, the third end of the Y-shaped body is coupled to the stoma via one or more stiches.

[0009] In some implementations, the method further includes preparing the vascular graft. In some implementations, the method further includes preparing the vascular graft in situ within a cadaver. In some implementations, the method further includes explanting the prepared vascular graft from the cadaver.

[0010] In some implementations, the method further includes implanting a first stent into the first conduit of the Y-shaped body and / or implanting a second stent into the second conduit of the Y-shaped body.Attorney Docket No. 103362-037WO1

[0011] In some implementations, the method further includes removing the first stent and / or the second stent from the Y-shaped body after an amount of time.

[0012] According to another implementation, a method of preparing a vascular graft is disclosed. The method includes providing a vascular graft including a Y-shaped body including a first conduit terminating at a first end, a second conduit terminating at a second end, and a third conduit terminating at a third end. Each of the first conduit, the second conduit, and the third conduit are in fluid communication with each other. The method further includes sterilizing and preserving the vascular graft via washing or infusing the vascular graft with a sterile solution including cryoprotectants. The method further includes cry opreserving the vascular graft to maintain cellular and structural integrity.

[0013] In some implementations, the vascular graft is preserved in situ within a cadaver, the method further including explanting the prepared vascular graft from the cadaver.

[0014] In some implementations, the method further includes implanting the vascular graft at a ureteral procedure site. In some implementations, the vascular graft provides for urinary diversion.

[0015] In some implementations, the method further includes coupling the first end of the Y-shaped body to a first ureter of the ureteral procedure site such that the first conduit is in fluid communication with the first ureter; coupling the third end of the Y-shaped body to a stoma defined through a body wall of a body such that the third conduit is in fluid communication with an exterior of the body.

[0016] According to another implementation, a vascular graft for a ureteral procedure site is disclosed. The graft includes a Y-shaped body including a first conduit terminating at a first end, a second conduit terminating at a second end, and a third conduit terminating at a third end. Each of the first conduit, the second conduit, and the third conduit are in fluid communication with each other. The first end of the Y-shaped body is configured to couple to a first ureter of the ureteral procedure site such that the first conduit is in fluid communication with the first ureter. The second end of the Y-shaped body is configured to couple to a second ureter of the ureteral procedure site such that the second conduit is in fluid communication with the second ureter. The third end of the Y-shaped body is configured to couple to a stoma defined through a body wall of a body such that the third conduit is in fluid communication with an exterior of the body.Attorney Docket No. 103362-037WO1

[0017] In some implementations, the vascular graft is prepared and derived from a portion of an aorta including branches into one or more iliac arteries.

[0018] Additional advantages will be set forth in part in the description which follows or may be learned by practice. The advantages will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive, as claimed.

[0019] Various objects, aspects, features, and advantages of the disclosure will become more apparent and better understood by referring to the detailed description and taken in conjunction with the accompanying drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The systems, methods, and devices are explained in even greater detail in the following drawings. The drawings are merely exemplary, and certain features may be used singularly or in combination with other features. The drawings are not necessarily drawn to scale.

[0021] FIG. 1 shows a vascular graft configured for urinary diversion, according to one implementation.

[0022] FIG. 2 shows a diagram of the vascular graft of FIG. 1 implanted in a body for urinary diversion, according to one implementation.

[0023] FIG. 3 shows a flowchart for a method of implanting a vascular graft, according to one implementation.DETAILED DESCRIPTION

[0024] Disclosed herein is an Allograft Bioengineered Conduit Device (ABCD) and method of surgical implantation. The allograft device is intended to replace the use of small bowel segments (ileum) or colon in bladder cancer (BC) patients undergoing radical cystectomy with pelvic lymphadenectomy.

[0025] The allograft device may include, for example, biocompatible cryopreserved vascular allograft material, with ureteral and skin attachments on opposite ends. In some implementations, the allograft device will have approximate dimensions of 20 x 5 x 5 cm andAttorney Docket No. 103362-037WO1 will be cylindrical in shape. The allograft device will remain in the body after implantation. Initially, ureteral stents may be used at the site of ureteral-allograft anastomosis for patency as per standard practice.

[0026] The disclosed allograft device and method of surgical implantation provides many technical advantages over existing devices and methods. For example, the disclosed device and method significantly alters the duration of surgery, hospital stay, readmissions, and reduces the immediate and long-term complications experienced by bladder cancer patients, improving their quality of life.

[0027] The disclosed method results in shorter surgical times, due in part to the shape of the allograft device matching that of the ureters and the bladder but mainly due to lack of the need for bowel harvest for urinary conduit. The disclosed method improves postoperative outcomes by reducing intestinal complications resulting from bowel related surgery, such as ileus, bowel obstruction, bowel anastomosis leak, and / or abdominal infections. The disclosed method provides faster recovery resulting in earlier discharge from the hospital and lesser readmission rates from lack of complications. Additionally, the disclosed method removes the long-term metabolic complications associated with bowel use such as excessive mucus production, metabolic acidosis, secondary malignancy etc.

[0028] Some existing allograft devices are provided in the vascular surgery field. For example, cadaveric cryoallograft devices such as the CyroArtery aortoiliac artery available from Artivion and RestoreFlow vascular allografts available from LeMaitre. However, no such allografts have been used in the treatment of bladder cancer - specifically as a novel urinary conduit. The use of such vascular grafts avoids the use of bowel segments and their associated complications. Given the proven biocompatibility, structural integrity, and infection-resistant properties of these FDA-approved grafts in vascular disease applications over many years, they possess the qualities of an ideal biomaterial for urinary diversion.

[0029] In some examples, the vascular allografts can be used for urinary diversion. For example, a first end of the Y-shaped allograft may be coupled to and in fluid communication a first ureter of a urinary system. A second end of the Y-shaped allograft may be coupled to and in fluid communication with a second ureter of a urinary system. A third end of the Y- shaped allograft in fluid communication with each of the conduits of the first and second ends of the Y-shaped allograft may be coupled to the skin (called a “stoma”). Thus, the first and second ureters may bypass the bladder and be coupled to a stoma, which may deposit fluid toAttorney Docket No. 103362-037WO1 the external environment (e.g., a collection bag coupled to the abdomen and the stoma defined therein).

[0030] FIG. 1 shows an aortoiliac graft 100, according to one implementation. The graft 100 includes a first conduit 102, a second conduit 104, and a third conduit 106 together forming a Y-shaped body. The first conduit 102, the second conduit 104, and the third conduit 106 are in fluid communication with each other. The first conduit 102 terminates at a first end 112. The second conduit 104 terminates at a second end 114. The third conduit 106 terminates at a third end 116.

[0031] FIG. 2 shows the graft 100 implanted in a body for urinary bypass. In particular, the first end 112 of the first conduit 102 is coupled to the first ureter of the ureteral procedural site. The second end 114 of the second conduit 104 is coupled to the second ureter. The third end 116 of the third conduit 106 is coupled to a stoma defined on the outer wall of the body, bypassing the bladder.

[0032] In some implementations, a stent may be implanted into the first conduit 102 and / or the second conduit 104. For example, the stent may maintain structural integrity of the conduit for a period of time. In some implementations, the stent is removed after a period of time.

[0033] The graft 100 may be prepared in situ within a cadaver before explaining the graft from the cadaver. For example, the graft 100 may be prepared by sterilizing and preserving the vascular graft via washing and / or infusing the graft with a sterile solution. The sterile solution may include cryoprotectants, wherein the graft 100 is cryopreserved to maintain cellular and structural integrity.

[0034] The graft 100 is implanted at a ureteral procedure site according to any one or more steps described herein. In one example, the graft 100 is implanting according to the method 200 shown in FIG. 3. At step 201, the method 200 includes providing a vascular graft comprising a Y-shaped body including a first, second, and third conduit. For example, the vascular graft may be a cryopreserved aortoiliac artery graft as described herein.

[0035] At step 202, the method 200 includes coupling the first end of the Y-shaped body to a first ureter of the ureteral procedure site. At step 203, the method 200 includes coupling the second end of the Y-shaped body to a second ureter of the ureteral procedure site. At step 204, the method 200 includes coupling the third end of the Y-shaped body to a stoma definedAttorney Docket No. 103362-037WO1 through a body wall of a body. The coupling in steps 202-204 may be performed via one or more sutures or stitches. Once coupled, the first, second, and third conduits are in fluid communication with each other to bypass the bladder of the ureteral procedure site. According to some implementations, the disclosed method includes preparing the vascular graft by, for example, sterilizing and preserving the vascular graft.Examples, Technical Advantages, and Discussion

[0036] Impact: MIBC has a 5-year survival rate of 72%, which decreases to 38% when it spreads to regional organs. Consequently, radical cystectomy and pelvic lymphadenectomy with urinary diversion has remained the standard-of-care to ensure the timely removal of the primary tumor. Urinary diversion using the bowel can be accomplished in two primary ways: a non-cutaneous continent diversion or a cutaneous incontinent diversion. The former involves refashioning a long (~60 cm) bowel segment to form a “neobladder” capable of storing and emptying urine through the urethra. The latter involves using a smaller (~20 cm) segment of the ileum, which is taken out of continuity and remodeled as a conduit for urine, with one end sutured to the skin as a uro-stoma and the other end serving as the point of ureteral attachment. These techniques are complex, and neither open nor robotic approaches have shown proven superiority over one another. This is largely because almost all complications arise from the use of small intestinal segments, a factor common to both robotic and open approaches. The necessity of disconnecting and reconnecting bowel segments poses short-term challenges. Moreover, the primary function of the bowel — to absorb gut contents — does not align well with the proper functioning of the urinary tract, leading to a myriad of long-term complications. These complications not only affect the recovery and well-being of patients but also impose a significant financial burden on the healthcare infrastructure.

[0037] Given these concerns, a handful of surgical teams and scientists have explored bladder regeneration and / or the use of external grafts to replace bowel segments as urinary conduits. However, all such experiments have failed to date. Table 1 provides a detailed summary of these grafting experiments, including the reasons for their failure.Attorney Docket No. 103362-037WO1

[0038] Table 1. Summary of Previous Grafting ExperimentsAttorney Docket No. 103362-037WO1

[0039] The disclosed Allograft Bioengineered Conduit Device (ABCD) and method of surgical use and implantation eliminates the need for small bowel segments in patients undergoing radical cystectomy for bladder cancer. It is the first implementation of an allograft for urinary diversion in comparison to prior grafts that were derived from synthetic material (Table 1). In some examples, the cryopreserved vascular allograft, specifically the aortoiliac graft, is repurposed to function as the urinary conduit. The proposed device, constructed from FDA-approved, biocompatible, cadaveric cryopreserved vascular allograft material, will have dimensions of approximately 20 x 5 x 5 cm and is designed to be a permanent implant within the body.

[0040] The properties of ABCD that make it a superior choice over previously utilized grafts include at least the following:A. Biocompatibility: Derived from natural cadaveric sources, these vascular grafts undergo a rigorous cry opreservation process to reduce immunogenicity (certification from the American Association of Tissue Banks). This minimizes the likelihood of complications such as contractures, stomal stenosis, and ureteral-conduit anastomotic strictures, which often result from tissue ingrowth and fibrotic reactions from surrounding tissues — primary reasons for the failure of prior experimental grafts.B. Structural Integrity: As mentioned above, stomal stenosis and contractures due to fibrotic reaction from surrounding tissues have been the major cause of failure in previous grafts, including in the only human trial to date (Bivalacqua et al). The vascular grafts are engineered to withstand aortic pressures, typically ranging from 80-120 mm Hg, which far exceed the pressures that these grafts will encounter from urine storage (internal pressure) or in situ tissue fibroblasts (external pressure) in their proposed use as urinary conduits. Further, in their use vascular grafts, they have already demonstrated their capacity to withhold these intrinsic and extrinsic pressures and maintain patency. Finally, the distinctive Y-shape of the aortoiliac grafts should facilitate a widely spatulated, watertight anastomosis of the ureters to the ABCD, enhancing functionality and patency of the anastomotic sites.C. Biostability: The non-biodegradable nature of these grafts ensures longevity and functional stability as urinary conduits.D. Infection-resistance: Cryopreserved allografts, primarily used in vascular surgery within infected fields, exhibit reduced infection rates attributed to cry opreservation andAttorney Docket No. 103362-037WO1 diminished antigenicity. Their reinfection rates of 4-8% are comparatively low, especially when benchmarked against other prosthetics.

[0041] Additional benefits of the disclosed Allograft Bioengineered Conduit Device (ABCD) and method of surgical use and implantation include: Reduction of short-term postoperative intestinal surgery-related complications such as ileus, bowel obstruction, bowel anastomotic leaks, and abdominal infections; Elimination of long-term metabolic complications associated with the use of bowel segments such as metabolic acidosis, renal failure, bone mineral loss, and the potential for secondary malignancies; Substantially shorter surgical times; Same day or postoperative day #1 discharge from the hospital; and Global healthcare cost-savings, from reduction in the length of hospital stay, readmission rates, and complications.Configuration of Certain Implementations

[0042] The construction and arrangement of the systems and methods as shown in the various implementations are illustrative only. Although only a few implementations have been described in detail in this disclosure, many modifications are possible (e.g., variations in sizes, dimensions, structures, shapes, and proportions of the various elements, values of parameters, mounting arrangements, use of materials, colors, orientations, etc.). For example, the position of elements may be reversed or otherwise varied, and the nature or number of discrete elements or positions may be altered or varied. Accordingly, all such modifications are intended to be included within the scope of the present disclosure. The order or sequence of any process or method steps may be varied or re-sequenced according to alternative implementations. Other substitutions, modifications, changes, and omissions may be made in the design, operating conditions, and arrangement of the implementations without departing from the scope of the present disclosure.

[0043] Although the figures show a specific order of method steps, the order of the steps may differ from what is depicted. Also, two or more steps may be performed concurrently or with partial concurrence. All such variations are within the scope of the disclosure.

[0044] It is to be understood that the methods and systems are not limited to specific synthetic methods, specific components, or to particular compositions. It is also to be understood that the terminology used herein is for the purpose of describing particular implementations only and is not intended to be limiting.Attorney Docket No. 103362-037WO1

[0045] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another implementation includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another implementation. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0046] “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. Throughout the description and claims of this specification, the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps. “Exemplary” means “an example of’ and is not intended to convey an indication of a preferred or ideal implementation. “Such as” is not used in a restrictive sense, but for explanatory purposes.

[0047] Disclosed are components that can be used to perform the disclosed methods and systems. These and other components are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these components are disclosed that while specific reference of each various individual and collective combinations and permutation of these may not be explicitly disclosed, each is specifically contemplated and described herein, for all methods and systems. This applies to all aspects of this application including, but not limited to, steps in disclosed methods. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific implementation or combination of implementations of the disclosed methods.

Claims

Attorney Docket No. 103362-037WO1WHAT IS CLAIMED IS:

1. A method of implanting a vascular graft at ureteral procedure site, the method comprising:(i) providing a vascular graft comprising a Y-shaped body comprising a first conduit terminating at a first end, a second conduit terminating at a second end, and a third conduit terminating at a third end, wherein each of the first conduit, the second conduit, and the third conduit are in fluid communication with each other;(ii) coupling the first end of the Y-shaped body to a first ureter of the ureteral procedure site such that the first conduit is in fluid communication with the first ureter;(iii) coupling the third end of the Y-shaped body to a stoma defined through a body wall of a body such that the third conduit is in fluid communication with an exterior of the body.

2. The method of claim 1, further comprising: coupling the second end of the Y-shaped body to a second ureter of the ureteral procedure site such that the second conduit is in fluid communication with the second ureter.

3. The method of claim 2, wherein the first and second ureters are in fluid communication with the stoma, bypassing a urinary bladder of the ureteral procedure site.

4. The method of claim 2, wherein the vascular graft provides for urinary diversion.

5. The method of claim 2, wherein the first end of the Y-shaped body is coupled to the first ureter via one or more stiches.

6. The method of claim 2, wherein the third end of the Y-shaped body is coupled to the stoma via one or more stiches.

7. The method of claim 1, further comprising: preparing the vascular graft.Attorney Docket No. 103362-037WO18. The method of claim 1, further comprising: preparing the vascular graft in situ within a cadaver.

9. The method of claim 8, further comprising explanting the prepared vascular graft from the cadaver.

10. The method of claim 2, further comprising: implanting a first stent into the first conduit of the Y-shaped body.

11. The method of claim 10, further comprising: removing the first stent from the Y- shaped body after an amount of time.

12. The method of claim 10, further comprising: implanting a second stent into the second conduit of the Y-shaped body.

13. A method of preparing a vascular graft, the method comprising:(i) providing a vascular graft comprising a Y-shaped body comprising a first conduit terminating at a first end, a second conduit terminating at a second end, and a third conduit terminating at a third end, wherein each of the first conduit, the second conduit, and the third conduit are in fluid communication with each other;(ii) sterilizing and preserving the vascular graft via washing or infusing the vascular graft with a sterile solution comprising cryoprotectants; and(iii) cry opreserving the vascular graft to maintain cellular and structural integrity.

14. The method of claim 13, wherein the vascular graft is preserved in situ within a cadaver, the method further comprising explanting the prepared vascular graft from the cadaver.

15. The method of claim 13, further comprising: implanting the vascular graft at a ureteral procedure site.

16. The method of claim 15, wherein the vascular graft provides for urinary diversion.Attorney Docket No. 103362-037WO117. The method of claim 16, further comprising: coupling the first end of the Y-shaped body to a first ureter of the ureteral procedure site such that the first conduit is in fluid communication with the first ureter; coupling the third end of the Y-shaped body to a stoma defined through a body wall of a body such that the third conduit is in fluid communication with an exterior of the body.

18. A vascular graft for a ureteral procedure site, the graft comprising: a Y-shaped body comprising a first conduit terminating at a first end, a second conduit terminating at a second end, and a third conduit terminating at a third end, wherein each of the first conduit, the second conduit, and the third conduit are in fluid communication with each other, wherein the first end of the Y-shaped body is configured to couple to a first ureter of the ureteral procedure site such that the first conduit is in fluid communication with the first ureter, wherein the second end of the Y-shaped body is configured to couple to a second ureter of the ureteral procedure site such that the second conduit is in fluid communication with the second ureter, and wherein the third end of the Y-shaped body is configured to couple to a stoma defined through a body wall of a body such that the third conduit is in fluid communication with an exterior of the body.

19. The vascular graft of claim 18, wherein the vascular graft is prepared and derived from a portion of an aorta including branches into one or more iliac arteries.

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