Bioengineered Lung Recellularization for Perfusable Microvasculature
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Solution Overview
Problem
Current methods for producing bioengineered lungs (BELs) fail to establish perfusable microvasculature networks capable of supporting tissue survival and withstanding physiological pressures, leading to issues like intravascular coagulation and pulmonary edema, limiting long-term survival post-transplantation.
Innovation Solution
A method involving the use of acellular lung scaffolds treated with growth factors, seeded with primary lung cells, and cultured in a bioreactor, optionally with immune cell reconstitution, to develop a functional BEL with a reconstituted immune system and developed microvasculature.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If BEL is transplanted without functional vascular tissue, then transplantation can be performed, but intravascular coagulation and pulmonary edema occur leading to failure
Solution Approach 1:
The patent applies preliminary action by pre-forming functional vascular networks within the BEL during the bioreactor culturing phase before transplantation. The vascular endothelial cells are seeded and cultured to develop mature, functional vasculature that can immediately handle physiological pressures and prevent coagulation upon implantation, rather than attempting to form vessels after transplantation.
Solution Approach 2:
The patent employs self-service by enabling the BEL to develop its own functional vascular system through autologous vascular endothelial cells that self-organize into perfusable networks during culturing. The system uses endogenous cell proliferation and differentiation to create the necessary vascular infrastructure without requiring external vascular connections at the time of transplantation.
2Reliability
If microvasculature networks are developed to support tissue survival, then tissue viability improves, but the complexity of producing perfusable networks increases
Solution Approach 1:
The patent applies self-service by allowing vascular endothelial cells to autonomously self-organize and form functional microvasculature networks during the bioreactor culturing process. The cells naturally proliferate, migrate, and assemble into tube-like structures that become perfusable vessels, eliminating the need for complex external guidance patterns or scaffolds.
Solution Approach 2:
The patent implements continuity of useful action by maintaining continuous bioreactor culturing conditions that promote uninterrupted vascular network development. The system provides continuous nutrient supply, oxygenation, and mechanical stimulation (such as fluid flow) throughout the culturing period, allowing vascular networks to progressively mature and become fully functional before transplantation.
3Ease of manufacture
If BEL is cultured without immune system reconstitution, then production process is simpler, but rejection risk increases post-transplantation
Solution Approach 1:
The patent applies preliminary action by reconstituting the immune system during the bioreactor culturing phase before transplantation. Immune cells are introduced and allowed to develop within the BEL, pre-establishing immunological compatibility and reducing the risk of acute rejection upon implantation, rather than addressing immune issues after transplantation.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The method produces BELs that survive long-term post-transplantation, develop functional alveolar and vascular tissues, and support collateral circulation without vascular anastomosis, with a reconstituted immune system and stable lung microbiome.
Implementation Method 1
treating the AC lung scaffold with one or more growth factors and platelet rich plasma which promote angiogenesis and the functionality of the BEL after transplantation
Implementation Method 2
vascular endothelial cells to form tube-like structures that self-organize into functional blood vessels
Implementation Method 3
treating the AC lung scaffold with one or more growth factors and platelet rich plasma which promote angiogenesis and the functionality of the BEL after transplantation
Data Source
AI summary
The present invention provides processes for producing a bioengineered lung (BEL) from an acellular lung matrix that has been treated with growth hormones, seeded with primary lung cells, and cultured in a bioreactor. Also provided are BELs and methods of transplanting the BEL into a subject in need of a lung transplant, and methods for using BELs for the study of the lung microbiome and its role in lung development and remodeling.