Transport and Lymphatic Uptake of Biotherapeutics Through Subcutaneous Injection

Han, Dingding; Rahimi, Ehsan; Aramideh, Soroush; Ardekani, Arezoo M.

doi:10.1016/j.xphs.2021.09.045

Cited by 16 publications

(16 citation statements)

References 59 publications

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“…In our previous works [11][12][13], the convective transport of drug solutes is driven by the interstitial fluid pressure (IFP) into the lymphatic system, which plays an important role in drug absorption through SC injection. The mechanical process of the injection and its effect on pressure build-up and relaxation are essential to understand the fluid flow and drug clearance at the injection site [12,14].…”

Section: Introductionmentioning

confidence: 99%

“…The poroelastic model is widely used to describe the deformation of biological tissues and hydrogels [12,14,19,20]. Our previous studies numerically investigate the contribution of large interstitial pressure to drug absorption during and after the injection [11,12]. A hybrid discrete-continuum vessel network model is developed to describe the diffusion and convection of drug solutes across the vessel wall [13].…”

Section: Introductionmentioning

confidence: 99%

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Solute Transport across the Lymphatic Vasculature in a Soft Skin Tissue

Han

Huang

Rahimi

et al. 2023

Biology

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Convective transport of drug solutes in biological tissues is regulated by the interstitial fluid pressure, which plays a crucial role in drug absorption into the lymphatic system through the subcutaneous (SC) injection. In this paper, an approximate continuum poroelasticity model is developed to simulate the pressure evolution in the soft porous tissue during an SC injection. This poroelastic model mimics the deformation of the tissue by introducing the time variation of the interstitial fluid pressure. The advantage of this method lies in its computational time efficiency and simplicity, and it can accurately model the relaxation of pressure. The interstitial fluid pressure obtained using the proposed model is validated against both the analytical and the numerical solution of the poroelastic tissue model. The decreasing elasticity elongates the relaxation time of pressure, and the sensitivity of pressure relaxation to elasticity decreases with the hydraulic permeability, while the increasing porosity and permeability due to deformation alleviate the high pressure. An improved Kedem–Katchalsky model is developed to study solute transport across the lymphatic vessel network, including convection and diffusion in the multi-layered poroelastic tissue with a hybrid discrete-continuum vessel network embedded inside. At last, the effect of different structures of the lymphatic vessel network, such as fractal trees and Voronoi structure, on the lymphatic uptake is investigated. In this paper, we provide a novel and time-efficient computational model for solute transport across the lymphatic vasculature connecting the microscopic properties of the lymphatic vessel membrane to the macroscopic drug absorption.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Solute Transport across the Lymphatic Vasculature in a Soft Skin Tissue

Han

Huang

Rahimi

et al. 2023

Biology

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“…However, these models focus on the material response and fluid pressure change in interstitial tissue, and do not model the changes of fluid pressures in blood vessels and lymphatic vessels or the drug transport induced by the material responses. Drug transport coupled with tissue deformation is also considered in some studies (Han et al., 2021 ; Hou et al., 2021 ; Zheng et al., 2021a ; Leng et al., 2022 ; Rahimi et al., 2022 ). Nevertheless, these studies apply a linear model to describe the lymphatic uptake assuming that the lymphatic fluid pressure is constant, and ignore changes in lymphatic pressure due to tissue deformation and fluid flow.…”

Section: Introductionmentioning

confidence: 99%

MPET ² : a multi-network poroelastic and transport theory for predicting absorption of monoclonal antibodies delivered by subcutaneous injection

Wang

Leng

et al. 2023

Drug Delivery

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Subcutaneous injection of monoclonal antibodies (mAbs) has attracted much attention in the pharmaceutical industry. During the injection, the drug is delivered into the tissue producing strong fluid flow and tissue deformation. While data indicate that the drug is initially uptaken by the lymphatic system due to the large size of mAbs, many of the critical absorption processes that occur at the injection site remain poorly understood. Here, we propose the MPET 2 approach, a multi-network poroelastic and transport model to predict the absorption of mAbs during and after subcutaneous injection. Our model is based on physical principles of tissue biomechanics and fluid dynamics. The subcutaneous tissue is modeled as a mixture of three compartments, i.e., interstitial tissue, blood vessels, and lymphatic vessels, with each compartment modeled as a porous medium. The proposed biomechanical model describes tissue deformation, fluid flow in each compartment, the fluid exchanges between compartments, the absorption of mAbs in blood vessels and lymphatic vessels, as well as the transport of mAbs in each compartment. We used our model to perform a high-fidelity simulation of an injection of mAbs in subcutaneous tissue and evaluated the long-term drug absorption. Our model results show good agreement with experimental data in depot clearance tests.

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“…Drug transport coupled with solid deformation is also considered in Han et al. ( 2021 ) and Rahimi et al. ( 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Mixed-dimensional multi-scale poroelastic modeling of adipose tissue for subcutaneous injection

Leng

Wang

Lucio

et al. 2022

Biomech Model Mechanobiol

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Subcutaneous injection of therapeutic monoclonal antibodies (mAbs) has gained increasing interest in the pharmaceutical industry. The transport, distribution and absorption of mAbs in the skin after injection are not yet well-understood. Experiments have shown that fibrous septa form preferential channels for fluid flow in the tissue. The majority of mAbs can only be absorbed through lymphatics which follow closely the septa network. Therefore, studying drug transport in the septa network is vital to the understanding of drug absorption. In this work, we present a mixed-dimensional multi-scale (MDMS) poroelastic model of adipose tissue for subcutaneous injection. More specifically, we model the fibrous septa as reduced-dimensional microscale interfaces embedded in the macroscale tissue matrix. The model is first verified by comparing numerical results against the full-dimensional model where fibrous septa are resolved using fine meshes. Then, we apply the MDMS model to study subcutaneous injection. It is found that the permeability ratio between the septa and matrix, volume capacity of the septa network, and concentration-dependent drug viscosity are important factors affecting the amount of drug entering the septa network which are paths to lymphatics. Our results show that septa play a critical role in the transport of mAbs in the subcutaneous tissue, and this role was previously overlooked.

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Transport and Lymphatic Uptake of Biotherapeutics Through Subcutaneous Injection

Cited by 16 publications

References 59 publications

Solute Transport across the Lymphatic Vasculature in a Soft Skin Tissue

Solute Transport across the Lymphatic Vasculature in a Soft Skin Tissue

MPET ² : a multi-network poroelastic and transport theory for predicting absorption of monoclonal antibodies delivered by subcutaneous injection

Mixed-dimensional multi-scale poroelastic modeling of adipose tissue for subcutaneous injection

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Transport and Lymphatic Uptake of Biotherapeutics Through Subcutaneous Injection

Cited by 16 publications

References 59 publications

Solute Transport across the Lymphatic Vasculature in a Soft Skin Tissue

Solute Transport across the Lymphatic Vasculature in a Soft Skin Tissue

MPET 2 : a multi-network poroelastic and transport theory for predicting absorption of monoclonal antibodies delivered by subcutaneous injection

Mixed-dimensional multi-scale poroelastic modeling of adipose tissue for subcutaneous injection

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Product

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MPET ² : a multi-network poroelastic and transport theory for predicting absorption of monoclonal antibodies delivered by subcutaneous injection