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Organ Biology

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The global trend for development of organ protection
device to reduce secondary warm ischemic injury
1），2）

Shinji Torai

1）, Eiji Kobayashi

1）
Department of Kidney Regenerative Medicine, Jikei University School of Medicine, 2）SCREEN Holdings Co., Ltd.

TOPICS〔Abstract〕 The issue of cold-stored donor kidneys falling into a secondary warm
ischemic state during vascular anastomosis in the recipient body has been alongstanding problem since the beginning of organ transplantation therapy. Theauthors have successfully developed an organ protector that suppresses secondary
warm ischemia in cold-stored kidneys by using insulating materials based on polymer
chemistry and thermodynamics. In this review, we introduced the development process
and the functions of the product, Organ Pocket, the world's first organ protector forkidney transplantation, which was successfully developed through the realization ofmedical-industrial collaboration.

Introduction

field of organ transplantation. Nonetheless, anastomosis is an extremely time-consuming procedure; there-Since the early days of organ transplantation, secondary ischemic injury during vascular anastomosis infore, reducing secondary warm ischemic injury is amajor issue.

the recipient body has been known to adversely affect

Kobayashi et al. were the first to develop a surgicalpostoperative donor organ function. Alexis Carrel, who

technique to perform anastomosis while maintaining

was awarded the Nobel Prize in Physiology or

circulation of the removed organ1）,2）. Since 2015,

Medicine in 1912 for his work on vascular suturing

SCREEN Holdings Co., Ltd. have been focusing on theand transplantation of blood vessels and organs, aimed

medical device business as a new field to explore, andto recirculate blood as quickly as possible by rapidly

have been researching and developing domesticallycompleting anastomosis of the donor organ. Organs re-produced organ perfusion and culture devices. In addi-

moved for transplantation are stored in cold conditions

tion, they began working on the development of pe-

to prevent deterioration due to auto-metabolism; how-ripheral devices as part of a joint industry-university

ever, once the organ is introduced into the body, it isresearch project. As a result of their research, they suc-

exposed to a secondary warm ischemic state until re-ceeded in developing the worldʼs first organ pocket tovascularization is completed, and blood recirculation

prevent secondary warm ischemia in the transplanted

begins. Therefore, transplant surgeons have focused onorgans.

refining their vascular anastomosis techniques andIn this paper, we introduce the worldʼs first Organ

quickly performing the procedure. Recipient surgeries

Pocket （Class I）medical device for transplantation,

have become less invasive, and speculative and robotic

which was successfully commercialized in Japansurgeries have become the focus of attention in thethrough industry-academia collaboration based on aCorresponding author; Eiji Kobayashi, Department of Kidney Regenerative Medicine, Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi,minato-ku, Tokyo, 105-8461, Japan
E-mail; qqhr7ct9k@river.ocn.ne.jp
Received; 2021/11/9
Accepted; 2021/11/24
This article is a parallel translation of the Japanese short review by Shinji Torai and Eiji Kobayashi in Organ Biology Vol.29, Issue 1, Page 39-45, 2022.

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47

Fig. 1 Initial stage of development of “Organ Protection Sheet” with heat shielding effect
A. Sheet made from everyday materials. The inner surface is made of HEATTECH®
cloth, and the outer surface is wrapped in Saran Wrap®.
B. Prototype type. The inside is made of polyethylene and the outside is made ofsilicon sheet.
C. Tested on a pig liver transplant.

global competition conducted during the development

summarizes the documents related to patents. Finally,of this product.

in 2020 and 2021, the company developed a patent application for containers of harvested organs.

Reason for Development

Global Competition

At the beginning stages of development in 2015, wecame up with the idea of an Organ Protection Sheet

In the January 2018 issue of the American Journal

with a thermal barrier effect, to prevent secondaryof Transplantation, the authors reported the results of awarm ischemia（Fig. 1）. In many medical device de-preclinical study using a porcine kidney transplantvelopments in academia, testing of new ideas tends tomodel of a thermal barrier sheet that actively cools thebe delayed because the materials and design are con-inside of the sheet（Fig. 3）3）. This idea was in line withsidered in detail first; however, from the beginning, we

the demands of the times, and was designed for robotic

repeated trials by hand using everyday items.

surgery with an active cooling function that allows

Simultaneously, we tested active cooling, which uses

cold ethanol to flow back to the inner surface of thecold water to cool the inside of the thermal barrier

sheet that encases the organ.

sheet.

The authors initially thought of commercializing

These organ protection devices, such as the draw-

this idea without presenting it at conferences or sub-string type that wraps the organs in a bag-like shape,

mitting papers until it was realized; however, they werewere developed while applying for intellectual proper-

surprised by the competitiveness in this field. In responsety patents, based on the companyʼs strategy. Fig. 2

to this article, we wrote a letter to Transplantation

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Fig. 2Intellectual property strategy for organ protection sheets with thermal barrier
effectPart of a patent strategy for organ protection using silicone and elastomer is described.
The patent for the protective sheet is registered and three other patent applications
have been published.

Fig. 3 Report on the intra-abdominal cooling system by MEIER et al.
A system to cool organs by actively circulating ethanol as a refrigerant fluid to suppress warm
ischemic injury in robotic assisted kidney transplantation. The results of temperature andpathological analysis at the time of kidney transplantation and blood flow confirmation by MRI
suggest that the system is more effective in protecting renal function after resumption of bloodflow than conventional methods in cases of system adaptation3）.
Adapted from Meier RPH et al. Intra-Abdominal Cooling System Limits Ischemia-Reperfusion
Injury During Robot-Assisted Renal Transplantation. Am J Transplant 2018;18（1）:53-62. 2017
（DOI: 10.1111/ajt.14399）, Figs. 1, 2. Copyright© 2017 The Authors. Used under the Creative
Commons Attribution-NonCommercial-NoDerivatives 4.0 International Public License（https://creativecommons.org/licenses/by-nc-nd/4.0/）

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49Fig. 4 K
 idney housing made of medical grade silicon
Photograph of a laparoscopic renal arteriovenous
anastomosis for a transplanted kidney. The upper partof the silicone container is open, and cold storage
solution can be dripped through the tube.4）
Adapted from Kobayashi E, Torai S et al. Intraabdominal Cooling System for the Transplanted Kidney.
Transplant Direct 2019;5（ 4）: e438. DOI:10.1097/
TXD.0000000000000882 （Intra-abdominal Cooling
System for the Transplanted Kidney: Transplantation
Direct（lww.com）Fig. 1. Copyright © 2019 The Authors.

Direct, in which we introduced a silicon organ fixation

completion of the vascular anastomosis（wearingdevice that could be used for long-term vascular anas-group, 21℃; control, 30℃）
. In the 7-day survival

tomosis, with cold preservation fluid flowing throughevaluation, one patient died of primary non-function

the organ even in the back shape（Fig. 4） .

（PNF）on day 1 with the conventional method, but the4）Subsequently, this group reported further studies

patient with the organ fixation device survived until 7

showing the effectiveness of using the device duringdays later, and serum BUN and creatinine returned tolaparotomy（Fig. 5） .

normal levels.

5）

The authors conducted research and development

Surprisingly, it was recently discovered that Khan etusing a porcine kidney transplant model, intending toal. in Australia worked on a similar project7）. They also

apply the material of this organ fixation device to clin-

attached an organ protection device（named Jacket ）ical kidney transplantation（Figure 6） .

to porcine kidneys to inhibit secondary ischemic injury6）

Initially, we developed an organ fixation device

and examined its insulating effect ex vivo. Using a 3D

made mainly of biocompatible and insulating silicon

printer, Khan et al. fabricated and tested prototypes ofmaterials for clinical transplantation. To verify the effi-silicon and urethane organ fixation devices. As a result,cacy of the developed product, we evaluated the sur-it was confirmed that the temperature of the donor kid-

face temperature of the donor kidney during vascular

ney after 30 min was maintained at〜13℃（control, 〜anastomosis and biochemical values at 7 days of survival

25℃; wearing group,〜12℃）, which was lower thanin a pig kidney transplantation model, using a donor

that of the conventional method, similar to the results

kidney with a 30-min circulatory arrest. Comparing

obtained by the authors.

the conventional method without the fixation device
and the case with the organ fixation device, there was adifference of approximately 9℃ at 30 min after the50

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Fig 5 D evelopment of a device to prevent secondary warm ischemia in thetransplanted kidney during vascular anastomosis
A chronological list of research reports on reducing warm ischemic injury during
vascular anastomosis in various countries.

Fig. 6 Effect of organ protective equipment on warm ischemic injury during vascular anastomosis
In a pig model, when donor kidneys were transplanted 30 minutes after blocking the renal artery, acomparison of cases with and without the use of organ protection devices showed that theintraoperative increase in kidney surface temperature was suppressed and the prognosis was improvedin the cases with the use of organ protection devices6）.
Reprinted from Transplant Proc 2019;51（5）. Torai S, et al, Reduction of Warm Ischemia Using a
Thermal Barrier Bag in Kidney Transplantation: Study in a Pig Model, P.1442-1450（DOI: 10.1016/
j.transproceed.2019.01.136.）. Fig. 2, 4. Copyright ©（2019）, with permission from Elsevier.

Toward the launch of the worldʼs firsttransplant organ protection bag

their high hardness and low elasticity. Therefore, theauthors used an elastomeric gel material as the original
material to protect the organs without damaging them,

Silicon materials have been used in many medical

while maintaining the high insulation properties anddevices because of their high biocompatibility; howev-conforming to the body. We succeeded in making it aser, they pose a risk of damage to organs because ofsoft and reversibly elastic as the human abdominal

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51Fig. 7 The worldʼs first organ protector “Organ Pocket” and performance test
A. Schematic view of the organ pocket made of ultra-soft elastomer. A. Overhead view of theOrgan Pocket, which is made mainly of transparent and biocompatible insulating material anddesigned to be suitable for the kidney. C. Temperature change during anastomosis with theOrgan Pocket. C. Temperature changes during anastomosis with and without the OrganPocket.

cavity. In addition, to respond to donor kidneys world-in blood BUN and creatinine was also observed, with awide, the average size of adult kidneys was calculated

maximum of 7.0 mg/L for BUN and 1.2 mg/L for cre-based on CT and MRI data from various countries

atinine in the target group and a maximum of 8.0 mg/（Fig. 7）.

L for BUN and 1.6 mg/L for creatinine in the control

Using pig kidneys, the following experiments weregroup. These results indicate that suppressing the heat-

conducted on the insulating and renoprotective effects

ing of the kidney during vascular anastomosis pre-of the newly developed organ pockets. Donor kidneys

serves its function after blood reperfusion.

that had been cold-stored at 4℃ were removed fromthe organ storage solution and placed on a stain-Conclusion

less-steel bathtub that had been warmed to 37℃,
mimicking an abdominal cavity. To measure the tem-At present, the basic evaluation of the Organ

perature change in the donor kidney, a thermocouple

Pocket has been completed, and a clinical study, titled

was inserted from the ureter to the renal pelvis, andA single-center, open-label, uncontrolled, single-armheated at 37℃ for 30 min. A cannula was inserted into

study on the safety and efficacy of the Organ Pocket

the renal artery, and whole blood from the donor pig

thermal barrier bag in kidney transplant recipient sur-was circulated and perfused with a tubing pump for 45gery（First in human study） is being conducted at themin to measure the blood BUN and creatinine levels.

Department of Gastroenterology and Transplant

The donor kidneys with（target group）and without

Surgery, Hiroshima University Hospital by Professor（control group）organ pockets were compared. As

Hideki Odan.

shown in Fig. 7C, the results of the temperature measurement showed that the center of the kidney in theAcknowledgments

target group was 16℃ after 30 min, while it reached
37℃ in only 5 min in the control group. The difference

The development of the Organ Pocket , an organ

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protector introduced in this paper, is the result of research on the development of medical devices at theSCREEN Holdings Corporation. We would like to express our gratitude to Mr. Kanta Kurauchi and the other members of the development team. Eiji Kobayashi
is an external technical advisor on medical devices for
the SCREEN Holdings Corporation. Authors would
like to thank Editage（www.editage.com）for English
language editing.
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Solution in Liver Transplantation. Transplant Direct 2017;3（4）:e141. doi: 10.1097/TXD.0000000000000656.
eCollection.
2）Kobayashi E, Yoshimoto S. Novel Triangular Tube for
Ischemia-Free Organ Transplantation. Transplant Direct
2019;5（4）:e435. doi: 10.1097/TXD.0000000000000874.
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3）Meier RPH, Piller V, Hagen ME, Joliat C, Buchs JB, Nastasi
A, Ruttimann R, Buchs NC, Moll S, Vallée JP, Lazeyras F,Morel P, Bühler L. Intra-Abdominal Cooling System Limits
Ischemia-Reperfusion Injury During Robot-Assisted Renal
Transplantation. Am J Transplant 2018;18（1）:53. doi:
10.1111/ajt.14399. Epub 2017 Jul. 24.
4）Kobayashi E, Torai S. Intra-Abdominal Cooling System for
the Transplanted Kidney. Transplant Direct 2019;5（4）:e438. doi: 10.1097/TXD.0000000000000882.
eCollection.
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M, Lazeyras F, Corpataux JM, Bühler L. Impact of an IntraAbdominal Cooling Device During Open Kidney
Transplantation in Pigs. Swiss Med Wkly. 2019;149:w20143.
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HC. Protection From the Second Warm Ischemic Injury inKidney Transplantation Using an Ex Vivo Porcine Modeland Thermally Insulating Jackets. Transplant Proc 2021;53（2）:750. doi: 10.1016/j.transproceed.2021.01.037. Epub2021 Feb. 11.