基于水凝胶粘合界面的可降解颅内压无线传感器研究

  颅脑损伤、脑出血等脑部疾病均会引起颅内压（intracranial pressure, ICP）的升高。当颅内压持续超过2 kPa时可能导致脑水肿、脑位移和脑缺血等一系列症状，并且其急性的上升将可能引起库欣反应，致使病人眩晕呕吐甚至死亡。因此，需要对颅脑疾病患者进行实时的颅内压监测，以便于医护人员及时发现并解决病症。临床上通常采用脑室内造口、脑硬膜外传感器等方法对其进行实时的监测。但以上设备由于其有线、侵入的特点不仅限制患者的行动还增加了患者受感染几率。并且在监测结束后，植入装置需要二次手术取出，增加了手术的风险。基于以上挑战，本研究采用串联谐振原理实现了器件的无线无源化，并利用可降解金属镁与聚己内酯（polycaprolactone, PCL）为软段的聚氨酯（polyurethane，PU）实现器件结构完全可降解。为了发挥器件的最佳检测性能，本研究在聚氨酯薄膜表面引入聚丙烯酸/N-羟基琥珀酰亚胺丙烯酸酯（poly(acrylic acid-co-acrylic acid N-hydroxysuccinimide ester), PAA-NHS）聚合物刷，使其与组织表面氨基发生酰胺化反应从而建立粘合界面，将器件与组织牢固结合。本研究报道了基于水凝胶粘合界面的可降解颅内压传感体系，实现颅内压的实时监测，并在无线无源传输、组织粘附、生物相容性、降解性等方面进行深入研究。

Craniocerebral injury, cerebral hemorrhage and other brain diseases can cause growing intracranial pressure (ICP). When the intracranial pressure exceeds 2 kPa, it can trigger a series of symptoms such as brain edema, brain displacement and cerebral ischemia; and a sharp rise in the ICP can lead to Cushing's reaction, resulting in dizziness, vomiting and even death. Therefore, it is necessary to monitor the ICP of patients with craniocerebral diseases, so that the disease could be detected and solved in time. In clinic, intraventricular and epidural sensors are usually used to monitor ICP. However, due to its wired and invasive characteristics, these equipments not only restrict the movement of patients, but also increases the probability of infection. In addition, after invasive monitoring, the implanted devices have to be removed through a secondary operation, which further increases the risk of surgery and cost. To solve these challenges, in this study, a wireless and passive ICP sensor was designed following the principle of series resonance. The structure of the sensor was completely degradable by virtue of the biodegradable magnesium and polyurethane (PU) bearing polycaprolactone (PCL) segments. In order to achieve the desirable detection performance of the device, poly(acrylic acid-co-N-hydroxysuccinimide acrylate) (PAA-NHS) polymer brushes were grafted on the surface of the polyurethane film, thus they could form amid groups with the amino groups in the tissue sides. This strategy offers an adhesive interface, enabling a robust integration of the device with the subcutaneous tissues. Overall, this study reports a biodegradable sensing system with an efficient adhesive interface that can be used for real-time monitoring of the intracranial pressure. Further, in-depth studies were carried out to assess the wireless passive transmission performance, tissue adhesion, biocompatibility and degradability of the sensing system.

[1] YIN J, HINCHET R, SHEA H, et al. Wearable Soft Technologies for Haptic Sensing and Feedback[J]. Advanced Functional Materials, 2020: 2007428.
[2] CHUNG H U, RWEI A Y, HOURLIER-FARGETTE A, et al. Skin-interfaced Biosensors for Advanced Wireless Physiological Monitoring in Neonatal and Pediatric Intensive-care Units[J]. Nature Medicine, 2020, 26(3): 418-429.
[3] CAPOBIANCO E, DOMINIETTO M. From Medical Imaging to Radiomics: Role of Data Science for Advancing Precision Health[J]. Journal of Personalized Medicine, 2020, 10(1): 15.
[4] 陈积义.腹内高压及腹腔间隙综合症的研究进展[J].大医生,2017,2(08):103-115.
[5] 史玉泉.颅内压增高[J].新医学,1975,1(2):118-124.
[6] 王立江,元小冬.有创颅内压监测技术在重型颅脑损伤患者中的应用价值[J].解放军医药杂志,2017,29(08):55-59.
[7] 张斌,栗洁,贾丛林.高血压脑出血外科治疗中颅内压监测及临床意义[J].浙江创伤外科,2012,17(03):376-377.
[8] 齐洪武,曾维俊,任胤朋,等.有创颅内压监测技术的研究进展[J].中国微侵袭神经外科杂志,2020,25(06):281-284.
[9] 武蒙蒙,胡红建,梅其勇.无创颅内压监测技术研究进展[J].第二军医大学学报,2021,42(08):897-902.
[10] PHAN H P. Implanted Flexible Electronics: Set Device Lifetime with Smart Nanomaterials[J]. Micromachines, 2021, 12: 157.
[11] KANG S K, MURPHY R, HWANG S W, et al. Bioresorbable Silicon Electronic Sensors for the Brain[J]. Nature, 2016, 530: 71-76.
[12] LU D, YAN Y, DENG Y, et al. Bioresorbable Wireless Sensors as Temporary Implants for In Vivo Measurements of Pressure[J]. Advanced Functional Materials, 2020, 30: 2003754.
[13] LU D, YAN Y, AVILA R, et al. Bioresorbable Wireless Passive Sensors as Temporary Implants for Monitoring Regional Body Temperature[J]. Advanced Healthcare Materials, 2020, 9: 2000942.
[14] YUK H, LU B, ZHAO X. Hydrogel Bioelectronics[J]. Chemical Society Reviews, 2019, 48: 1642-1667.
[15] SHIN J, YAN Y, BAI W, et al. Bioresorbable Pressure Sensors Protected with Thermally Grown Silicon Dioxide for the Monitoring of Chronic Diseases and Healing Processes[J]. Nature Biomedical Engineering, 2019, 3: 37-46.
[16] 江基尧.中国颅脑创伤颅内压监测专家共识[J].中华神经外科杂志,2011,10:1073-1074.
[17] SCHWAB S, SCHELLINGER P, WERNER C, et al. Neurointensive[M].雷霆,译.武汉:湖北科学技术出版社,2014:67-74.
[18] 曹美鸿.颅内压增高的诊治颅内压增高的原因与机理[J].医师进修杂志,1984,11:1-3.
[19] 粟秀初.颅内压增高与脑疝形成及其发病机理[J].医师进修杂志,1984,11:6-8.
[20] 高亮,周良辅,黄峰平,等.脑室内颅内压持续监测和阶梯式治疗重型颅脑外伤[J].中华神经外科杂志,2007,23(07):507-509.
[21] 彭发坤.颅内压监测术后颅内感染危险因素分析[J].浙江创伤外科,2021,26(02):207-209.
[22] CYROUS A, O’NEAL B, FREEMAN W D. New approaches to bedside monitoring in stroke[J]. Expert Review of Neurotherapeutics, 2012, 12(8): 915-928.
[23] CARTER C C. Miniature Passive Pressure Pransensor for Implanting in the Eye[J]. IEEE-Transactions on Biomedical Engineering, 1967, 14(2): 74-83.
[24] HUANG Q, DONG L, WANG L, et al. LC Passive Wireless Sensors Toward a Wireless Sensing Platform: Status, Prospects, and Challenges[J]. Journal of Microelectromechanical Systems, 2016, 25(5): 822-841.
[25] CHEN L, TEE C, BAO Z, et al. Continuous Wireless Pressure Monitoring and Mapping with Ultra-small Passive Sensors for Health Monitoring and Critical Care[J]. Nature Communication, 2014, 5: 5028.
[26] LEE J, IHLE S J, Pellegrino G S, et al. Stretchable and Suturable Fibre Sensors for Wireless Monitoring of Connective Tissue Strain[J]. Nature Electronics, 2021, 4: 291-301.
[27] RUTH S R A, FEIG V R, TRAN H, et al. Microengineering Pressure Sensor Active Layers for Improved Performance[J]. Advanced Functional Materials, 2020, 30: 2003491.
[28] YUN G, TANG S, LU H, et al. Hybrid-Filler Stretchable Conductive Composites: From Fabrication to Application[J]. Small Science, 2021, 1: 2000080.
[29] RUTH S R A, BEKER L, TRAN H, et al. Rational Design of Capacitive Pressure Sensors Based on Pyramidal Microstructures for Specialized Monitoring of Biosignals[J]. Advanced Functional Materials, 2020, 30: 1903100.
[30] RUTH S R A, BAO Z. Designing Tunable Capacitive Pressure Sensors Based on Material Properties and Microstructure Geometry[J]. ACS Applied Materials and Interfaces, 2020, 12(52): 58301-58316.
[31] PENG S, BLANLOEUIL P, WU S, et al. 3D Printing: Rational Design of Ultrasensitive Pressure Sensors by Tailoring Microscopic Features[J]. Advanced Materials Interfaces, 2018, 5: 1800403.
[32] ZHANG J, YE S, LIU H. 3D Printed Piezoelectric BNNTs Nanocomposites with Tunable Interface and Microarchitectures for Self-powered Conformal Sensors[J]. Nano Energy, 2020, 77: 105300.
[33] WAN Y, QIU Z, HONG Y, et al. A Highly Sensitive Flexible Capacitive Tactile Sensor with Sparse and High-Aspect-Ratio Microstructures[J]. Advanced Electronic Materials, 2018, 4: 1700586.
[34] PANG Y, ZHANG K, YANG Z, et al. Epidermis Microstructure Inspired Graphene Pressure Sensor with Random Distributed Spinosum for High Sensitivity and Large Linearity[J]. ACS Nano, 2018, 12(3): 2346-2354.
[35] JIA J, HUANG G, DENG J, et al. Skin-inspired Flexible and High-sensitivity Pressure Sensors based on rGO Films with Continuous-gradient Wrinkles[J]. Nanoscale, 2019, 11(10): 4258-4266.
[36] LIANG X, QI Y, ZHEN P, et al. Design and Preparation of Quasi-spherical Salt Particles as Water-Soluble Porogens to Fabricate Hydrophobic Porous Scaffolds for Tissue Engineering and Tissue Regeneration[J]. Materials Chemistry Frontiers, 2018, 2: 1539-1553.
[37] LIANG X, CHEN G, LIN S, et al. Bioinspired 2D Isotropically Fatigue-Resistant Hydrogels[J]. Advanced Materials, 2022, 34: 2107106.
[38] VISSER C W, AMATO D N, MUELLER J, et al. Architected Polymer Foams via Direct Bubble Writing[J]. Advanced Materials, 2019, 31: 1904668.
[39] ZHAO T, LI T, CHEN L, et al. Highly Sensitive Flexible Piezoresistive Pressure Sensor Developed Using Biomimetically Textured Porous Materials[J]. ACS Appl Mater Interfaces, 2019, 11(32): 29466-29473.
[40] MOHAN S S. Simple Accurate Expressions for Planar Spiral Inductances[J]. IEEE Journal of Solid-state Circuits, 1999, 34(10): 1419-1424.
[41] ROSENGREN L, BACKLUND Y, SJOSTROM T, et al. A System for Wireless Intra-ocular Pressure Measurements Using a Silicon Micromachined Sensor[J]. Journal of Micromechanics and Microengineering, 1992, 2(202): 202-204.
[42] BOUTRY C M, BEKER L, KAIZAWA Y, et al. Biodegradable and Flexible Arterial-pulse Sensor for the Wireless Monitoring of Blood Flow[J]. Nature Biomedical Engineering, 2019, 3(1): 47-57.
[43] KALIDASAN V, YANG X, XIONG Z, et al. Wirelessly Operated Bioelectronic Sutures for the Monitoring of Deep Surgical Wounds[J]. Nature Biomedical Engineering, 2021, 5: 1217-1227.
[44] FEINER R. DVIR T. Tissue–electronics Interfaces: From Implantable Devices to Engineered Tissues[J]. Nature Reviews Materials, 2017, 3: 17076.
[45] FAMM K, LITT B, TRACEY K, et al. A Jump-start for Electroceuticals[J]. Nature, 2013, 496: 159-161.
[46] MAX O C. Engineering and Surgical Advancements Enable More Cognitively Integrated Bionic Arms[J]. Science Robotics, 2021, 6(68): 3123.
[47] CHORTOS A, LIU J, BAO Z. Pursuing Prosthetic Electronic Skin[J]. Nature Materials, 2016, 15: 937-950.
[48] YUK H, LU B, ZHAO X. Hydrogel Bioelectronics[J]. Chemical Society Reviews, 2019, 48: 1642-1667.
[49] NATHAN A, AHNOOD A, COLE M, et al. Flexible Electronics: The Next Ubiquitous Platform[J]. Proceedings of the IEEE, 2012, 100(Special Centennial Issue): 1486-1517.
[50] YANG S, SHIM J H, CHO H, et al. Hetero-Integration of Silicon Nanomembranes with 2D Materials for Bioresorbable Wireless Neurochemical System[J]. Advanced Materials, 2022: 2108203.
[51] YIN L, BOZLER C, HARBURG D V, et al. Materials and Fabrication Sequences for Water Soluble Silicon Integrated Circuits at the 90 nm Node[J]. Applied Physics Letters, 2015, 106: 014105.
[52] DAGDEVIREN C, HWANG S W, SU Y, et al. Transient, Biocompatible Electronics and Energy Harvesters Based on ZnO[J]. Small, 2013, 9: 3398-3404.
[53] GAO J, CHEN S, TANG D, et al. Mechanical Properties and Degradability of Electrospun PCL/PLGA Blended Scaffolds as Vascular Grafts[J]. Transactions of Tianjin University, 2019, 25: 152-160.
[54] ASHAMMAKHI N, HERNANDEZ A L, UNLUTURK B D, et al. Biodegradable Implantable Sensors: Materials Design, Fabrication, and Applications[J]. Advanced Functional Materials, 2021, 31: 2104149.
[55] BOUTRY C M, KAIZAWA Y, SCHROEDER B C, et al. A Stretchable and Biodegradable Strain and Pressure Sensor for Orthopaedic Application[J]. Nature Electronics, 2018, 1: 314-321.
[56] WANG L, LU C, YIN L, et al. A Fully Biodegradable and Self-electrified Device for Neuroregenerative Medicine[J]. Science Advances, 2020, 6: eabc6686.
[57] GUO H, D'ANDREA D, ZHAO J, et al. Advanced Materials in Wireless, Implantable Electrical Stimulators that Offer Rapid Rates of Bioresorption for Peripheral Axon Regeneration[J]. Advanced Functional Materials, 2021, 31: 2102724.
[58] KIM H S, YANG S, JANG T M, et al. Bioresorbable Silicon Nanomembranes and Iron Catalyst Nanoparticles for Flexible, Transient Electrochemical Dopamine Monitors[J]. Advanced Healthcare Materials, 2018, 7: 1801071.
[59] KANG S, MURPHY R, HWANG S, et al. Bioresorbable Silicon Electronic Sensors for the Brain[J]. Nature, 2016, 530: 71-76.
[60] GOFFIN J M, PITTET P, CSUCS G, et al. Focal Adhesion Size Controls Tensiondependent Recruitment of α-Smooth Muscle Actin to Stress Fibers[J]. Journal of Cell Biology, 2006, 171: 259-268.
[61] CHOI S, HAN S I, JUNG D, et al. Highly Conductive, Stretchable and Biocompatible Ag–Au Core–sheath Nanowire Composite for Wearable and Implantable Bioelectronics[J]. Nature Nanotechnology, 2018, 13: 1048-1056.
[62] LEE S, FRANKLIN S, HASSANI F, et al. Nanomesh Pressure Sensor for Monitoring Finger Manipulation Without Sensory Interference[J]. Science, 2020, 370(6519): 966-970.
[63] LIU J, ZHANG X, LIU Y, et al. Intrinsically stretchable electrode array enabled in vivo electrophysiological mapping of atrial fibrillation at cellular resolution[J]. Proceedings of the National Academy of Sciences, 2020, 117(26): 14769-14778.
[64] COSTERTON J, MONTANARO L, ARCIOLA C. Biofilm in Implant Infections: Its Production and Regulation[J]. International Journal of Artificial Organs, 2005, 28: 1062-1068.
[65] YANG Q, WEI T, YIN R T, et al. Photocurable Bioresorbable Adhesives as Functional Interfaces Between Flexible Bioelectronic Devices and Soft Biological Tissues[J]. Nature Materials, 2021, 20: 1559-1570.
[66] DENG J, YUK H, WU J, et al. Electrical Bioadhesive Interface for Bioelectronics[J]. Nature Materials, 2021, 20: 229-236.
[67] YUK H, WU J, SARRAFIAN T L, et al. Rapid and Coagulation-independent Haemostatic Sealing by a Paste Inspired by Barnacle Glue[J]. Nature Biomedical Engineering, 2021, 5: 1131-1142.
[68] ZHANG K, CHEN X, XUE Y, et al. Tough Hydrogel Bioadhesives for Sutureless Wound Sealing, Hemostasis and Biointerfaces[J]. Advanced Functional Materials, 2021: 2111465.
[69] LIU X, LIU J, LIN S, et al. Hydrogel Machines[J]. Materials Today, 2020, 36: 102-124.
[70] WONG T S, KANG S, TANG S, et al. Bioinspired Self-repairing Slippery Surfaces with Pressure-stable Omniphobicity[J]. Nature, 2011, 477: 443-447.
[71] JACQUELINE L, HARDING, MELISSA M, et al. Combating Medical Device Fouling[J]. Trends in Biotechnology, 2014, 32(3): 140-146.
[72] BANERJEE I, PANGULE R C, KANE R S, et al. Antifouling Coatings: Recent Developments in the Design of Surfaces That Prevent Fouling by Proteins, Bacteria, and Marine Organisms[J]. Advanced Materials, 2011, 23: 690-718.
[73] LIU Q, NIAN G, YANG C, et al. Bonding Dissimilar Polymer Networks in Various Manufacturing Processes[J]. Nature Communications, 2018, 9: 846.
[74] YU Y, YUK H, PARADA G A, et al. Hydrogels: Multifunctional “Hydrogel Skins” on Diverse Polymers with Arbitrary Shapes[J]. Advanced Materials, 2019, 31: 1807101.
[75] 黄晶晶,任伊宾,张炳春,等.镁及镁合金的生物相容性研究[J].稀有金属材料与工程,2007,36(06):1102-1105.