Chemical functionality of multidomain peptide hydrogels governs early host immune response

Abstract

Multidomain Peptide (MDP) hydrogels are nanofibrous materials with many potential biomedical applications. The peptide sequence design of these materials offers high versatility and allows for the incorporation of various chemical functionalities into the nanofibrous scaffold. It is known that host response to biomaterials is strongly affected by factors such as size, shape, stiffness, and chemistry. However, there is a lack of fundamental understanding of the host response to different MDP hydrogels. In particular, it is unknown what effect the chemical functionality displayed on the nanofiber has on biological activity. Here we evaluated the early inflammatory host response to four MDP hydrogels displaying amines, guanidinium ions, and carboxylates in a subcutaneous injection model. While all the studied peptide materials possess similar nanostructure and physical properties, they trigger markedly different inflammatory responses. These were characterized by immunophenotyping of the cellular infiltrate using multi-color flow cytometry. The negativelycharged peptides elicit minimal inflammation characterized by tissue-resident macrophage infiltration, fast remodeling, and no collagen deposition or blood vessel formation within the implants. In contrast, the positively-charged peptides are highly infiltrated by immune cells, are remodeled at a slower rate, promote angiogenesis, and result in a high degree of collagen deposition. The presence of dynamic cell phenotypes characterizes the inflammation caused by the lysine-based peptide, including inflammatory monocytes, macrophages, and lymphoid cells, which is seen to be resolving over time. The arginine-based hydrogel shows higher inflammatory response with a persistent and significant infiltration of polymorphonuclear myeloid-derived cells, even ten days after implantation. This understanding of the immune response to peptide biomaterials improves our ability to design effective materials and to tailor their use for specific biomedical applications.

Recent Advances in Bioplastics: Application and Biodegradation

“…In tissue engineering applications, biopolymers have proven useful in replacing biogenic materials that could induce an immunogenic reaction due to non-specific host response [136][137][138]. Polymer composition and the possibility of introducing reactive functionality widens the potential of using biopolymers in this field [139].…”

Recent Progress in the Design and Application of Supramolecular Peptide Hydrogels in Cancer Therapy

“…In contrast, the positively-charged peptides were highly infiltrated by immune cells, were remodeled at a slower rate, would promote angiogenesis, and resulted in a high degree of collagen deposition. [131] These studies showed that the biological activity of the peptide-based hydrogels could be modulated at different levels from molecular design to hydrogel composition, which facilitates their biomedical applications.…”

Current Progress in Cross-Linked Peptide Self-Assemblies

“…Peptide fibers composed of natural amino acids with high biocompatibility have recently been developed in view of practical applications. Typical examples are peptide fibers developed by Hartgerink that contain repeated hydrophilic serine (S) and hydrophobic isoleucine (L) peptide sequences forming β -sheets as a self-assembly unit ( Figure 2 b) [ 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. Functional peptides can be incorporated to the termini of the peptide fibers forming “double domain-type peptide fibers” where the self-assembly unit and the functional part can be designed individually.…”

“…It was also confirmed that peptide fibers were formed, even when leucine is replaced to phenylalanine, tyrosine, or tryptophan [ 42 ]. Since the self-assembly unit is composed of neutral amino acid residues, charged amino acids can be incorporated to the self-assembly part [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. Peptide fibers containing repeated cationic arginine, hydrophobic alanine, anionic aspartic acid, and hydrophobic alanine residues (RADA sequence) have been reported by Zhang [ 55 ].…”

“…In pioneer works, amphiphilic peptides having hydrophobic alkyl chain at the termini of hydrophilic peptides have been designed, and their fundamental properties and applications to biomaterials have been investigated [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Currently, both amphiphilic peptides and other peptide-based self-assembly units have been found, enabling the design of peptide fibers with a variety of functions [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , …”