췌장액 누출 감지용 녹말 기반 에어로겔 시스템 개발 = Development of a Starch-Based Aerogel System for Pancreatic Leakage Detection

국문 초록 (Abstract)

췌장십이지장절제술(Pancreaticoduodenectomy, PD)은 팽대부 주위 악성 종양의 유일한 근치적 치료법이나, 여전히 높은 수술 후 합병증 발생률(30~50%)을 보이는 고위험 수술이다. 다양한 합병증 중에서도 췌장-공장 문합부위에서 아밀라아제가 풍부한 췌장액이 새어 나오는 수술 후 췌장루(Postoperative Pancreatic Fistula, POPF)는 가장 치명적인 합병증으로 꼽힌다. 복강 내로 누출된 활성 췌장 효소는 주변 조직과 혈관을 부식시키는 자가 소화(Autodigestion)를 유발하여, 복강 내 농양, 패혈증, 그리고 높은 사망률을 동반하는 수술 후 대량 출혈(Post-pancreatectomy hemorrhage)과 같은 심각한 2차 합병증을 초래한다.
현재의 췌장루 진단은 배액관을 통해 수집된 체액의 아밀라아제 농도를 중앙 검사실에서 분석하는 방식에 의존하고 있다. 그러나 이러한 방식은 검체 채취부터 결과 확인까지 상당한 시간 지연(Time-lag)이 발생하여, 급격히 진행되는 합병증에 대한 즉각적인 대처를 어렵게 한다. 또한, 장기간의 배액관 유치는 환자의 거동을 제한하고 역행성 감염의 원인이 된다. 이러한 임상적 난제를 해결하기 위해, 본 학위논문에서는 췌장액 누출을 실시간으로, 그리고 직관적으로 감지할 수 있는 생분해성 전분-셀룰로오스 나노섬유(CNF) 복합 에어로젤 센서를 제안한다.
본 연구에서는 천연 전분 소재가 가지는 본질적인 수분 불안정성을 극복하기 위해, 템포(TEMPO) 산화된 CNF를 보강재로 도입하는 새로운 제조 공정을 확립하였다. CNF 네트워크는 전분 매트릭스 내에서 물리적 지지체 역할을 하여, 효소의 접근성은 유지하면서도 습윤 환경에서의 기계적 안정성을 획기적으로 향상시켰다. 최적화된 에어로젤은 정상 체액 환경(~100 U/L)에서는 안정성을 유지하나, 누출 환경(>300 U/L)에서는 빠르게 분해되는 선택적 반응성을 나타내었다.
나아가, 본 연구는 개발된 소재를 무선 수동형(Wireless Passive) LC 공진 회로와 통합하여 활용할 수 있음을 입증하였다. 효소 분해에 따른 에어로겔의 유전율 변화와 구조적 붕괴를 공진 주파수 변화로 변환함으로써, 향후 체내 수술 부위를 연속적으로 감시할 수 있는 모니터링 기술의 기반을 마련하였다.

다국어 초록 (Multilingual Abstract)

Surgical resection remains the only potential curative modality for pancreatic ductal adenocarcinoma (PDAC) and other periampullary malignancies. Among the surgical options, pancreaticoduodenectomy (PD), commonly known as the Whipple procedure, represents the standard of care for tumors located in the pancreatic head. Despite significant advancements in operative techniques and perioperative management, PD is characterized by a high complexity and remains associated with substantial morbidity rates ranging from 30% to 50%. The success of this procedure is frequently compromised by the failure of the pancreaticojejunostomy (PJ), the reconstruction site where the remnant pancreas is anastomosed to the jejunum.
The most formidable and life-threatening complication arising from anastomotic failure is Postoperative Pancreatic Fistula (POPF). POPF is defined by the leakage of amylase-rich pancreatic fluid into the abdominal cavity. Unlike other surgical fluids, extravasated pancreatic juice contains activated proteolytic enzymes capable of digesting surrounding tissues and vascular structures. This autodigestion can precipitate severe clinical sequelae, including intra-abdominal abscesses, sepsis, and massive post-pancreatectomy hemorrhage (PPH), which is the leading cause of procedure-related mortality. Consequently, the early detection of pancreatic fluid leakage is critical for preventing the progression from a biochemical leak to a clinically severe complication.
Current clinical paradigms for detecting POPF are predominantly retrospective. Diagnosis relies on the intermittent laboratory analysis of amylase levels in drainage fluid collected via percutaneous drains, typically performed on postoperative days 1, 3, and subsequently as indicated. This conventional approach suffers from a significant diagnostic time-lag; by the time amylase elevation is confirmed and clinical symptoms manifest, substantial tissue damage or vascular erosion may have already occurred. This "reactive" monitoring strategy highlights an urgent unmet need for a "proactive" diagnostic modality capable of providing continuous, real-time surveillance of the anastomotic site.
To address these clinical challenges, this dissertation presents a novel, biodegradable sensing platform designed for the immediate detection of POPF. We developed a starch–cellulose nanofiber (CNF) composite aerogel engineered to undergo rapid, programmed structural degradation specifically in the presence of pathological amylase concentrations (>300 U/L), which are indicative of clinically significant leakage.
A critical limitation of native starch in biomedical applications is its intrinsic hydrophilicity, leading to premature disintegration in wet physiological environments. To overcome this, a reinforcing network of TEMPO-oxidized CNF was incorporated into the matrix. This modification significantly enhances the wet-state mechanical integrity of the aerogel, ensuring stability in non-pathological fluids while maintaining high sensitivity to enzymatic degradation. Furthermore, this study demonstrates the integration of this amylase-responsive aerogel with a wireless passive LC resonant circuit. Furthermore, this study demonstrated the feasibility of integrating the developed material with a wireless passive LC resonant circuit. By transducing enzyme-induced changes in the aerogel’s dielectric properties and structural degradation into shifts in resonant frequency, this work establishes a foundation for future monitoring technologies capable of continuously tracking postoperative conditions inside the body.

목차 (Table of Contents)

• Chapter 1 1
• Introduction 1
• 1.1 Evolution and Challenges of Pancreaticoduodenectomy 1
• 1.1.1 Pioneering Efforts and Standardization 1
• 1.1.2 From Mortality to Morbidity : The Shift in Clinical Focus 2
• 1.2 Clinical Significance and Postoperative Complications 2
• 1.2.1 Pathophysiology of POPF : pH Dependence and Enzymatic Activation 2
• 1.2.2 Secondary Complications and the Imperative for Early Detection 3
• 1.2.3 Current Trends and Limitations in Anastomotic Monitoring 4
• 1.3 Conventional Clinical Amylase Diagnostic Methods and Limitations 5
• 1.4 Recent research trends 6
• 1.5 Design Strategy of Starch-CNF Aerogel-Based Sensing Platform 7
• Chapter 2 8
• Experimental sections 8
• 2.1 Starch based aerogel reinforced by CNF : Moisture stability and enzyme degradation tests 8
• 2.1.1 Materials 8
• 2.1.2 Preparation of Starch-Based Aerogel 8
• 2.1.3 Characterization of Aerogel Porosity (FE-SEM and Stereomicroscopy) 9
• 2.1.4 Biodegradation Behavior Analysis (Weight Loss Test) 9
• 2.1.5 UVVis Absorbance Analysis 10
• 2.1.6 Stability of Aerogel in Solution (IodinePolysaccharide Complex) 11
• 2.1.7 Analysis of Aerogel Degradation as a Function of Amylase Concentration (DNS Reagent Reducing Sugar Assay) 12
• 2.2 Dynamic mechanical analysis of Aerogel 12
• 2.3 RF coil-based resonant frequency detection 13
• 2.3.1 Measurement setup of wireless pancreatic leakage sensor 13
• 2.3.2 Analysis of results on wireless measurement 14
• 2.4 Clinical Validation of Practical Applicability 15
• Chapter 3 16
• Results and discussion 16
• 3.1 Implementation of Starch Aerogels for Rapid, In-Situ Leakage Assessment 16
• 3.2 Structure of Starch and Degradation Mechanism by Amylase 17
• 3.3 Advantages of Porous Aerogel in Amylase Detection 19
• 3.4 CNF Incorporation for the Enhancement of Mechanical Stability 23
• 3.3 Quantitative evaluation of performance enhancements induced by CNF incorporation 27
• 3.5 Degradation Behavior of Starch-Based Aerogels Depending on Amylase 34
• 3.6 Clinical Applicability and Feasibility of Wireless Sensor Application 37
• 3.7 Effect of Starch Concentration on the Porosity of Starch-Based Aerogels 40
• Chapter 4 42
• Conclusion 42
• Reference 44
• 국문 초록 54