Research

Parenchymal–mesenchymal interactions are crucial during lung tissue development as well as maintaining homeostasis in normal condition and regeneration after injury. Deficient repairs after the injuries might lead to over activation of fibroblasts and excessive deposition of extracellular matrix (ECM), causing tissue remodeling and organ dysfunction if go awry. The increased mechanical stress rooted in ECM remodeling together with stretch and shear stress owing to spontaneous breathing are known to influence cell state. The link between the cell-ECM cross-talk and the resulting mechanical phenotype associated with disease presentation, including changes of extracellular structure and stiffness, remains unclear. Here we propose to employ and develop a versatile three-dimensional organoid platform enabling multiplex photonic and mechanical probing to study the physical and physiological mechanisms underlie and co-regulate cell-cell interactions in homeostasis, repair, and remodeling. A series of observation tools, including multiphoton microscope (second harmonic imaging microscope and two-photon microscope), confocal microscope, and quantitative differential phase contrast imaging will be developed and employed. Mechanical properties of the cell and its microenvironment will be accessed using varies microscopic tools and rheology analysis. We hope the technologies developed and knowledge gained in this study, can be the foundation of our future researches into the causes, treatments and prevention of lung diseases for translational applications.

細胞與間質的相互作用在呼吸系統的組織發育，以及維持健康狀況下的平衡狀態和損傷後的再生過程中至關重要。細胞損傷後若修復不足，可能會導致纖維細胞過度活化和細胞外基質 (ECM) 過度沉積，甚至會導致組織重組和器官功能障礙。源於 ECM 重組的機械應力增加以及由自主呼吸引起的拉伸和剪切應力目前已知會影響細胞狀態。然而細胞與間質的相互作用和由此產生疾病表現相關表現（包括細胞外基質結構和硬度的變化）之間的關聯尚不清楚。在此研究中，我們將開發一系列顯微影像及生物力學觀察方法,如多光子顯微鏡、多光子顯微鏡 、量化相位差顯微鏡 、光切片螢光顯微鏡 、共軛焦顯微鏡等一系列觀察工具結合細胞流變學分析和細胞及其微環境的機械特性等。並利用此肺部三維類組織觀察平台研究體內平衡、修復和重塑中細胞間和間質間相互作用的基礎和共同調節的物理和生理機制以及疾病表現相關的間質與細胞結構的變化。我們期待這項研究中開發的技術和獲得的知識可以用於未來研究慢性呼吸系統疾病和癌症相關轉譯醫學的研究肺部疾病的原因、治療和預防的基礎。

As the first optical interface of the ocular system, cornea is responsible for refractive convergence and protection. It functions as the first barrier against pathogens and external forces, and bears internal stress and overall distortion of the eye. Changes of the mechanical cues and microenvironment owing to trauma or diseases may impair the vision and attribute to further damages of the eye. The cornea is an avascular, transparent tissue that consists of five distinct layers: the epithelium, Bowman’s layer, stroma, Descemet’s membrane, and endothelium. Upon injury, the mechanical properties of the cornea undergo significant changes, numerous growth factors and cytokines are released into the stromal space, which promotes the differentiation of quiescent corneal keratocytes into myofibroblasts. The stromal compartment has been shown to stiffen substantially in the days after an injury. Here we propose to investigate the endothelial/epithelial–stromal communication under the influence of mechanical environments.

角膜作為眼系統的第一個光學界面，負責屈光和保護功能。它作為抵禦病原體和外力的第一道屏障，承受眼睛的內應力和整體變形。由於外傷或疾病引起的機械信號和微環境的變化可能會損害視力並導致眼睛進一步受損。角膜是一種無血管的透明組織，由五個不同的層組成：上皮、鮑曼層、基質、後彈力層和內皮。受傷後，角膜的力學性會發生顯著變化，大量生長因子和細胞因子釋放到基質空間，促進靜止的角膜細胞向肌成纖維細胞分化。在受傷後的幾天內，基質已被證明會顯著變硬。我們研究機械環境對角膜細胞的功能和訊息傳遞的影響。

Catheter angiography, employed across various organs such as abdominal viscera, cerebral vessels, and coronary arteries, serves as a gold standard diagnostic tool for vascular diseases, involving minimally invasive procedures. This method requires physician’s familiar with human vascular anatomy to guide catheter placement into target vessels and to determine appropriate contrast agent injection rates and volumes based on blood flow velocity and volume. During catheter placement, unforeseen endothelial damage may occur, particularly susceptible to iatrogenic arterial dissection, for which electrically injecting high-viscosity iodinated contrast agents is proposed in the literature as a mechanism.

In our study, we will use computational fluid dynamics models to calculate the forces (including shear and normal forces) exerted by catheter-injected contrast agents on vessel walls during angiography. We will vary parameters such as catheter angles, contrast agent viscosity, and flow rates to determine optimal and safe injection conditions, aiming to enhance the procedure's safety. The second part of the research involves ex-vivo experiments using biological tissues to validate the applicability of the computational model in biological tissues.

Our goal is to establish an ideal angiography model that integrates readily accessible computed tomography images of patient arteries, allowing personalized medical care based on our developed model. This research also aims to innovate catheter designs to further improve the safety of minimally invasive examinations.

經導管血管攝影運用於人體各種器官，包含腹部臟器、腦血管、心臟冠狀動脈等等，是血管疾患的標準診斷工具，是一種微創侵入性的檢查。該方法需要執行醫師熟知人體血管解剖構造，將導管置放至目標血管，並且根據該血管之血流流速及流量，選擇適當之顯影劑注射速率及體積。在置放導管的過程中，血管內皮可能發生不預期的受損，此一受損處為發生醫源性動脈剝離之弱點所在，對此區域以電動注射器輸注高黏滯性的含碘顯影劑，是文獻上對於醫源性動脈剝離發生所立論的機轉。

本研究中，我們將利用流體力學模型，計算血管攝影中，導管注射顯影劑對血管壁所造成的正向力與剪切力，並改變導管角度、顯影劑黏滯性、流速等參數，以求得適當且安全的注射條件，以提升此項檢查之安全性。在第二部分的研究中，我們將使用生物組織進行於活體之外的實驗，以驗證流體力學模型計算之結果於生物組織上的可運用性。

我們預期可建立出一理想的血管攝影模式，未來將病患在臨床上容易取得之電腦斷層影像，將其動脈立體幾何析出，導入我們所建之模型，得以為病患建立個人化醫療。這項研究的發現希望也藉此研發一種導管設計，進一步提升微創檢查的安全性。