Adhesive Tissue Engineered Scaffolds: Mechanisms and Applications

Abstract

A variety of suture and bioglue techniques are conventionally used to secure engineered scaffold systems onto the target tissues. These techniques, however, confront several obstacles including secondary damages, cytotoxicity, insufficient adhesion strength, improper degradation rate, and possible allergic reactions. Adhesive tissue engineering scaffolds (ATESs) can circumvent these limitations by introducing their intrinsic tissue adhesion ability. This article highlights the significance of ATESs, reviews their key characteristics and requirements, and explores various mechanisms of action to secure the scaffold onto the tissue. We discuss the current applications of advanced ATES products in various fields of tissue engineering, together with some of the key challenges for each specific field. Strategies for qualitative and quantitative assessment of adhesive properties of scaffolds are presented. Furthermore, we highlight the future prospective in the development of advanced ATES systems for regenerative medicine therapies.

Keywords: adhesive tissue engineering scaffold; bone regeneration; cardiac regeneration; cartilage regeneration; nerve regeneration; scaffold; tissue regeneration; wound repair.

FIGURE 1

Summary of different mechanisms of adhesion of tissue engineering scaffolds. Created with BioRender.com.

FIGURE 2

Different methods to assess adhesion strength. Created with BioRender.com.

FIGURE 3

Application of adhesive tissue engineering scaffold (ATES) in nerve repair. (A) Mechanism of Hydrogel Formation. (B) Transforming from prepolymer solution to hydrogel state. (C) Mechanism of adhesion between the hydrogel and the nerve epineurium. (D) Schematic demonstrating the application of ATES in vivo. Reconstructed with permission from Zhou et al. (2016).

FIGURE 4

Application of adhesive tissue engineering scaffolds (ATESs) in cartilage repair. (A) PDA-CS-PAM adhesive scaffold to regenerate cartilage. (a) Mechanism of PDA-CS complex fabrication. (b) Mechanism of PDA-CS-PAM hydrogel formation. (c) Schematic demonstration of the application of adhesive scaffold in vivo. (d) Cell repellence of CS-PAM hydrogel. (e) Promotion of cell adhesion to the hydrogel by addition of PDA. (B) Adhesive microgel systems for cartilage tissue engineering. (a) Assembly of microspheres induced by 4-arm PEG-NHS. (b) Assembled NHSA-microgels: (i) Compressive modulus of NHSA micro and bulk hydrogels by unconfined compression test; (ii) NHSA microgels on a spatula and under microscope (scale bar: 100 μm). (c) In vitro testing of adhesion ability: (i) Hollow gelatin hydrogel; (ii,iii) Injection of untreated microgels into the middle of the hollow hydrogel and no adhesion after 90 min; (iv,v) Injection of PEG-NHS treated microgel suspension into the middle of the hollow hydrogel and adhesion after incubation. (d) Demonstration of adhesion mechanism between microgels and tissue. **P < 0.01. Reconstructed with permissions from Fanyi et al. (2018) and Han et al. (2018).

FIGURE 5

Application of adhesive tissue engineering scaffolds (ATESs) in cornea repair. (A) Mechanism of hydrogel formation. (B) Application of ATES: (i) Corneal defect; (ii) Scaffold application; (iii) Epithelial healing; (iv) Regeneration. (C) Injection of prepolymer into injured cornea. (D) Demonstration of GelCORE hydrogel. (E–G) Compressive stress-strain curve (E), compressive moduli (F), and elastic moduli (G) for GelCORE hydrogels at varied concentration and crosslinking time. (H) Water content of GelCORE hydrogel after different crosslinking times at 37°C. (I) GelCORE degradation in collagenase type II at 37°C. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Reconstructed with permission from Shirzaei Sani et al. (2019).

FIGURE 6

Application of adhesive tissue engineering scaffolds (ATESs) in skin tissue repair. (A) GelMA hydrogel formation and application to skin wounds. (B) Representative TEM image of HA/miR-223^∗ NPs with ratio of 325:1 (w/w) in DPBS. (C) Representative confocal image of Cy5.5-labeled (red) NPs in hydrogel. (D) Elastic modulus of hydrogels containing different NP concentrations. (E) Compressive modulus of hydrogels with different NP concentrations. **P < 0.01 and ****P < 0.0001. Reconstructed with permission from Saleh et al. (2019).

FIGURE 7

Application of adhesive tissue engineering scaffolds (ATESs) in cardiac tissue repair. (A) Fabrication of electrospun cardiopatches, soaking in Irgacure solution, addition of Bio-IL, followed by UV crosslinking for 5 min. (B) GelMA/Bio-IL cardiopatch photo-crosslinked on explanted rat heart, demonstrating adequate adhesion (red arrows) to the heart tissue. (C) Wound closure test to test the adhesion strength of cardiopatches on the explanted rat heart (as substrate). (D) Quantification of the patch adhesion strength, consisting of 10% (w/v) gelMA and at varying concentrations of Bio-IL. (E) Images of gelMA/Bio-IL cardiopatch with 10% gelMA and 66% Bio-IL, crosslinked onto the defect site of explanted rat heart, to measure the burst pressure. (F) Quantification of the burst pressure. (G) H&E staining of patch-tissue interface, demonstrating a strong bonding of the hydrogel to the murine myocardium. (H,I) Ex vivo analysis of the threshold voltage of gelMA/Bio-IL cardiopatches at varying Bio-IL concentrations. *P < 0.05, ****P < 0.001 and ****P < 0.0001. Reconstructed with permission from Walker et al. (2019).

FIGURE 8

Application of adhesive tissue engineering scaffolds (ATESs) in bone tissue engineering. (A) Demonstration of SF@TA@HAP hydrogel formation. (B) Demonstration of adhesion and stretchability of SF@TA@HAP scaffold. (C) Demonstration of the flexibility and malleability of the hydrogel. (D) Glue filaments in the bone structure, connecting mineralized collagen fibrils. (E) Representative SEM image of the filaments in the SF@TA@HAP hydrogel. (F) Modulus of SF@TA@HAP hydrogel under repeated application of 100 and 0.1% strain. (G) AFM mechanical testing of SF@TA@HA, PMMA, and CPC. Bar graphs show the quantified values of dissipated energy during the separation step. (H) Results of mechanical testing of SF@TA@HA, PMMA, and CPC samples. Bar graphs show the quantified toughness. Reconstructed with permission from Bai et al. (2020).