Development of Enzymatic-Resistant and Compliant Decellularized Extracellular Matrixes via Aliphatic Chain Modification for Bladder Tissue Engineering

Abstract

Here, we report the design and development of highly stretchable, compliant, and enzymatic-resistant transiently cross-linked decellularized extracellular matrixes (dECMs) (e.g., porcine small intestine submucosa/dSIS, urinary bladder matrix/dUBM, bovine pericardium/dBP, bovine dermis/dBD, and human dermis/dHD). Specifically, these dECMs were modified with long aliphatic chains (C9, C14, and C18). Upon modification, dECMs became significantly resistant to enzymatic degradation for extended periods, showed increased water contact angle (>20%–90%), and stretched >200% than their control counterparts. Modified dECMs are compliant, undergoing 100% elongation at only 0.3–0.5 MPa of applied tensile stress (∼10%–25% of their control counterparts), similar to the control bladder tissue. Furthermore, modified dECMs remain structurally stable at the physiological temperature with increased storage and loss modulus values but decreased tan δ values compared to their control counterparts. Although modification reduces cell adhesion, the gene expressions in polarized macrophages remain unchanged (e.g., TGFβ, CD163, and CD86), except for the modified bovine pericardium (dBP) where a significant decrease in TNFα gene expression is observed. When implanted in the rat subcutaneous model, modified dECMs degraded relatively slowly and did not cause significant fibrotic tissue formation. The numbers of pro-regenerative macrophages increased to several folds in a later time point of evaluation. Modified dECM also supported the bladder wall regeneration with formations of the urothelium, lamina propria, blood vessels, and muscle bundles and reduced the occurrence of calculi formation by 50% in a rat bladder augmentation model. We anticipate that the enhanced stretchability, compliance, and physiological stability of dECMs indicate their suitability for urologic tissue regeneration.

Injectable Xenogeneic Dental Pulp Decellularized Extracellular Matrix Hydrogel Promotes Functional Dental Pulp Regeneration

“…Furthermore, the correlation between the degradation or remodeling rate of dECM hydrogels and the tissue regeneration rate remains an aspect warranting further investigation. Research has indicated that the degradation rate of dECM materials can be regulated via the addition of specific biological compounds or chemical modifications [85,86]. Conversely, the notable combination of high osteogenic activity and a slow degradation rate observed in the high-concentration dECM hydrogel implies its potential as a scaffold for bone tissue regeneration.…”

The application of small intestinal submucosa in tissue regeneration

“…Furthermore, Shivang Sharma et al achieved successful bladder regeneration utilizing SIS which had been modified by long aliphatic chains (C9, C14, and C18). This modification increased the SIS's resistance to enzymes and subsequently reduced the incidence of stone formation by 50% in a rat bladder enlargement model [ 139 ]. Li-Ping Huang et al described the production of multifunctional patches composed of PCA/SIS for mending urinary tract defects.…”

Research progress of biomaterials and innovative technologies in urinary tissue engineering

“…In another study, to overcome the poor expansibility and rapid degradation of decellularized extracellular matrixes (dECMs), including SIS and BAM, the transient crosslinking between dECMs and long-chain aliphatic molecules was developed. And dECMs were covalently linked to one end of the polymeric chains, while other molecules could interact at the other end through weak interactions, such as dipole-dipole forces ( Sharma et al, 2022 ). Additionally, some other composite nanofibrous patches or scaffolds composed of PLA/gelatin or HA/PLA/PCL have also been generated to evaluate the critical potential of replacing damaged or diseased bladder and urethra ( Liu et al, 2020a ; Wang et al, 2022 ).…”