Self-assembling Peptide Hydrogels Research Articles

Logic-Based Strategy for Spatiotemporal Release of Dual Extracellular Vesicles in Osteoarthritis Treatment.

To effectively treat osteoarthritis (OA), the existing inflammation must be reduced before the cartilage damage can be repaired; this cannot be achieved with a single type of extracellular vesicles (EVs). Here, a hydrogel complex with logic-gates function is proposed that can spatiotemporally controlled release two types of EVs: interleukin 10 (IL-10)+ EVs to promote M2 polarization of macrophage, and SRY-box transcription factor 9 (SOX9)+ EVs to increase cartilage matrix synthesis. Following dose-of-action screening, the dual EVs are loaded into a matrix metalloporoteinase 13 (MMP13)-sensitive self-assembled peptide hydrogel (KM13E) and polyethylene glycol diacrylate/gelatin methacryloyl-hydrogel microspheres (PGE), respectively. These materials are mixed to form a "microspheres-in-gel" KM13E@PGE system. In vitro, KM13E@PGE abruptly released IL-10+ EVs after 3 days and slowly released SOX9+ EVs for more than 30 days. In vivo, KM13E@PGE increased the CD206+ M2 macrophage proportion in the synovial tissue and decreased the tumor necrosis factor-α and IL-1β levels. The aggrecan and SOX9 expressions in the cartilage tissues are significantly elevated following inflammation subsidence. This performance is not achieved using anti-inflammatory or cartilage repair therapy alone. The present study provides an injectable, integrated delivery system with spatiotemporal control release of dual EVs, and may inspire logic-gates strategies for OA treatment.

A Rapid Self-Assembling Peptide Hydrogel for Delivery of TFF3 to Promote Gastric Mucosal Injury Repair.

Self-assembled peptide-based nanobiomaterials exhibit promising prospects for drug delivery applications owing to their commendable biocompatibility and biodegradability, facile tissue uptake and utilization, and minimal or negligible unexpected toxicity. TFF3 is an active peptide autonomously secreted by gastric mucosal cells, possessing multiple biological functions. It acts on the surface of the gastric mucosa, facilitating the repair process of gastric mucosal damage. However, when used as a drug, TFF3 faces significant challenges, including short retention time in the gastric mucosal cavity and deactivation due to degradation by stomach acid. In response to this challenge, we developed a self-assembled short peptide hydrogel, Rqdl10, designed as a delivery vehicle for TFF3. Our investigation encompasses an assessment of its properties, biocompatibility, controlled release of TFF3, and the mechanism underlying the promotion of gastric mucosal injury repair. Congo red/aniline blue staining revealed that Rqdl10 promptly self-assembled in PBS, forming hydrogels. Circular dichroism spectra indicated the presence of a stable β-sheet secondary structure in the Rqdl10 hydrogel. Cryo-scanning electron microscopy and atomic force microscopy observations demonstrated that the Rqdl10 formed vesicle-like structures in the PBS, which were interconnected to construct a three-dimensional nanostructure. Moreover, the Rqdl10 hydrogel exhibited outstanding biocompatibility and could sustainably and slowly release TFF3. The utilization of the Rqdl10 hydrogel as a carrier for TFF3 substantially augmented its proliferative and migratory capabilities, while concurrently bolstering its anti-inflammatory and anti-apoptotic attributes following gastric mucosal injury. Our findings underscore the immense potential of the self-assembled peptide hydrogel Rqdl10 for biomedical applications, promising significant contributions to healthcare science.

Impact of Glycosylation on Self-Assembled Peptide Hydrogels

Impact of Glycosylation on Self-Assembled Peptide Hydrogels

Self-assembling peptide hydrogel scaffold integrating stem cell-derived exosomes for infected bone defects

Infected bone defect (IBD) is a great challenge in orthopedics, which involves in bone loss and infection. Here, a self-assembling hydrogel scaffold (named AMP-RAD/EXO), integrating antimicrobial peptides(AMPs), RADA16 and BMSCs exosomes with an innovative strategy, is developed and applied in IBD treatment for sustained antimicrobial ability, accelerating osteoblasts proliferation and promoting bone regeneration. AMPs present an excellent ability to inhibit infection, RADA16 is a self-assembling peptide hydrogel for AMPs delivery, and BMSCs exosomes can promote the bone regeneration. The prepared AMP-RAD/EXO exhibited a polyporous 3D structure for imbibition of BMSCs exosomes and migration of osteoblasts. In vitro studies indicate AMP-RAD/EXO can inhibit the growth of Staphylococcus aureus, accelerate the proliferation and migration of BMSCs. More importantly, in vivo results also prove that AMP-RAD/EXO exhibit an excellent effect on IBD treatment. Thus, the prepared AMP-RAD/EXO provides a multifunctional scaffold concept for bone tissue engineering technology.

Peptide-Based Hydrogel for Nanosystems Encapsulation: the Next Generation of Localized Delivery Systems for the Treatment of Intestinal Inflammations.

Conventional therapies for inflammatory bowel diseases are mainly based on systemic treatments which cause side effects and toxicity over long-term administration. Nanoparticles appear as a valid alternative to allow a preferential accumulation in inflamed tissues following oral administration while reducing systemic drug exposure. To increase their residence time in the inflamed intestine, the nanoparticles are here associated with a hydrogel matrix. A bioadhesive peptide-based hydrogel is mixed with nanoemulsions, creating a hybrid lipid-polymer nanocomposite. Mucopenetrating nanoemulsions of 100nm are embedded in a scaffold constituted of the self-assembling peptide hydrogel product PuraStat. The nanocomposite is fully characterized to study the impact of lipid particles in the hydrogel structure. Rheological measurements and circular dichroism analyses are performed to investigate the system's microstructure and physical properties. Biodistribution studies demonstrate that the nanocomposite acts as a depot in the stomach and facilitates the slow release of the nanoemulsions in the intestine. Efficacy studies upon oral administration of the drug-loaded system show the improvement of the disease score in a mouse model of intestinal inflammation.

Structural Consequences of Introducing Bioactive Domains to Designer β-Sheet Peptide Self-Assemblies.

We applied solid- and solution-state nuclear magnetic resonance spectroscopy to examine the structure of multidomain peptides composed of self-assembling β-sheet domains linked to bioactive domains. Bioactive domains can be selected to stimulate specific biological responses (e.g., via receptor binding), while the β-sheets provide the desirable nanoscale properties. Although previous work has established the efficacy of multidomain peptides, molecular-level characterization is lacking. The bioactive domains are intended to remain solvent-accessible without being incorporated into the β-sheet structure. We tested for three possible anticipated molecular-level consequences of introducing bioactive domains to β-sheet-forming peptides: (1) the bioactive domain has no effect on the self-assembling peptide structure; (2) the bioactive domain is incorporated into the β-sheet nanofiber; and (3) the bioactive domain interferes with self-assembly such that nanofibers are not formed. The peptides involved in this study incorporated self-assembling domains based on the (SL)6 motif and bioactive domains including a VEGF-A mimic (QK), an IGF-mimic (IGF-1c), and a de novo SARS-CoV-2 binding peptide (SBP3). We observed all three of the anticipated outcomes from our examination of peptides, illustrating the unintended structural effects that could adversely affect the desired biofunctionality and biomaterial properties of the resulting peptide hydrogel. This work is the first attempt to evaluate the structural effects of incorporating bioactive domains into a set of peptides unified by a similar self-assembling peptide domain. These structural insights reveal unmet challenges in the design of highly tunable bioactive self-assembling peptide hydrogels.

How Chromophore Labels Shape the Structure and Dynamics of a Peptide Hydrogel.

Biocompatible and functionalizable hydrogels have a wide range of (potential) medicinal applications. The hydrogelation process, particularly for systems with very low polymer weight percentages (<1 wt %), remains poorly understood, making it challenging to predict the self-assembly of a given molecular building block into a hydrogel. This severely hinders the rational design of self-assembled hydrogels. In this study, we demonstrate the impact of an N-terminal group on the self-assembly and rheology of the peptide hydrogel hFF03 (hydrogelating, fibril forming peptide 03) using molecular dynamics simulations, oscillatory shear rheology, and circular dichroism spectroscopy. We find that the chromophore and even its specific regioisomers have a significant influence on the microscopic structure and dynamics of the self-assembled fibril, and on the macroscopic mechanical properties. This is because the chromophore influences the possible salt bridges, which form and stabilize the fibril formation. Furthermore, we find that the solvation shell fibrils by itself cannot explain the viscoelasticity of hFF03 hydrogels. Our atomistic model of the hFF03 fibril formation enables a more rational design of these hydrogels. In particular, altering the N-terminal chromophore emerges as a design strategy to tune the mechanic properties of these self-assembled peptide hydrogels.

Hybrid Self-Assembled Peptide Hydrogels Promote Skin Wound Healing in Diabetic Mice

Hybrid Self-Assembled Peptide Hydrogels Promote Skin Wound Healing in Diabetic Mice

P1223 Lactobacillus rhamnosus GG/p40 encapsuled cationic host defense peptide play protective roles on immune-related colitis by inducing differentiation and immune suppression of regulatory T cells

Abstract Background The immune-related colitis (IRC) is the most prominent in immune-related adverse events (irAE). The association between gut microbiota and IRC development has been revealed. Our study aimed to explore the protective effect and mechanism of the probiotic Lactobacillus rhamnosus GG (LGG) and its secretory protein p40 on IRC. The self-assembled cationic host defense peptide (CHDP) hydrogel was applied to protect oral p40 protein from digestive damage and target enriched the site of colitis. Methods The IRC model mice were intervened with LGG by gavage (i.g.), p40 by enema (en.), or p40 encapsuled by CHDP (i.g.). The T cell phenotype of colonic lamina propria mononuclear cells (LPMC) was measured by flow cytometry. The indocyanine green (ICG) encapsuled by CHDP was gavage in IRC model mice, the distribution of CHDP was monitored by fluorescence signals imaging via IVIS, to assess the adhesive effect of CHDP in mice colitis. In vitro, the proportion of regulatory T cells (Treg) differentiated was measured by LGG supernatant co-cultured with CD4+ naïve T cells, and the division index of CD4+T cells was measured by LGG supernatant co-cultured with CD4+T cells and Treg (CD4+T cells: Treg=1:1) by carboxyfluorescein succinimidyl ester (CFSE) staining test. Results Compared with DSS+anti-PD-1+anti-CTLA-4 IRC model group, LGG (i.g.) group had lower weight loss, DAI score, histopathological score, relative IL-6 and TNF-α mRNA level, IL-6 and TNF-α concentration and higher colon length (P&amp;lt;0.05) (Fig.1A-L). P40 (en.) group had lower weight loss, DAI score, histopathological score and higher colon length (P&amp;lt;0.05) (Fig.1M-T). CHDP+p40 (i.g.) group had lower weight loss, DAI score, histopathological score, relative IL-6 and TNF-α mRNA level, IL-6 concentration and higher colon length (P&amp;lt;0.05) (Fig.1M-W). The percentages of CD25+FoxP3+Treg/CD4+T cells of colonic LPMC in LGG, p40 (en.), and CHDP+p40 (i.g.) group were significantly higher than IRC model group (P&amp;lt;0.05) (Fig.1X-Z, α). The average 28hr-residual rate of fluorescence imaging radiance in IRC-CHDP+ICG group was higher than both NC-CHDP+ICG and IRC-ICG group (Fig.2β-δ), and the average radiance of colon in IRC-CHDP+ICG group was also the highest (P&amp;lt;0.05) (Fig.2ε-ζ). In vitro, LGG 107 CFU/mL, 108 CFU/mL and 5 × 108 CFU/mL (P&amp;lt;0.05) could significantly promote Treg differentiation with concentration dependent manner (Fig.2η-ι), and the suppression of Treg on CD4+T cells with lower division index compared with control group (Fig.2κ). Conclusion LGG/p40 played protective role by promoting the differentiation and immune suppression of Treg cells in IRC. CHDP hydrogel could protect p40 protein from the digestive damage, and target enriched the inflamed lesion to improve the efficacy.

Engineering Self-Assembling Peptide Hydrogel to Enhance the Capacity of Dendritic Cells to Activate In Vivo T-Cell Immunity.

The efficacy of the dendritic cell (DC) has failed to meet expectations thus far, and crucial problems such as the immature state of DCs, low targeting efficiency, insufficient number of dendritic cells, and microenvironment are still the current focus. To address these problems, we developed two self-assembling peptides, RLDI and RQDT, that mimic extracellular matrix (ECM). These peptides can be self-assembled into highly ordered three-dimensional nanofiber scaffold structures, where RLDI can form gelation immediately. In addition, we found that RLDI and RQDT enhance the biological function of DCs, including releasing antigens sustainably, adhering to DCs, promoting the maturation of DCs, and increasing the ability of DC antigen presentation. Moreover, peptide hydrogel-based DC treatment significantly achieved prophylactic and treatment effects on colon cancer. These results have certain implications for the design of new broad-spectrum vaccines in the future.

Self-assembled peptide hydrogels for the treatment of diabetes and associated complications

Diabetes is a widespread epidemic that includes a number of comorbid conditions that greatly increase the chance of acquiring other chronic illnesses. Every year, there are significantly more people with diabetes because of the rise in type-2 diabetes prevalence. The primary causes of illness and mortality worldwide are, among these, hyperglycemia and its comorbidities. There has been a lot of interest in the creation of peptide-based hydrogels as a potentially effective platform for the treatment of diabetes and its consequences. Here, we emphasize the use of self-assembled hydrogel formulations and their unique potential for the treatment/management of type-2 diabetes and its consequences. (i.e., wounds). Key aspects covered include the characteristics of self-assembled peptide hydrogels, methods for their preparation, and their pre-clinical and clinical applications in addressing metabolic disorders such as type-2 diabetes.

Neuronal Replenishment via Hydrogel-Rationed Delivery of Reprogramming Factors.

The central nervous system's limited capacity for regeneration often leads to permanent neuronal loss following injury. Reprogramming resident reactive astrocytes into induced neurons at the site of injury is a promising strategy for neural repair, but challenges persist in stabilizing and accurately targeting viral vectors for transgene expression. In this study, we employed a bioinspired self-assembling peptide (SAP) hydrogel for the precise and controlled release of a hybrid adeno-associated virus (AAV) vector, AAVDJ, carrying the NeuroD1 neural reprogramming transgene. This method effectively mitigates the issues of high viral dosage at the target site, off-target delivery, and immunogenic reactions, enhancing the vector's targeting and reprogramming efficiency. In vitro, this vector successfully induced neuron formation, as confirmed by morphological, histochemical, and electrophysiological analyses. In vivo, SAP-mediated delivery of AAVDJ-NeuroD1 facilitated the trans-differentiation of reactive host astrocytes into induced neurons, concurrently reducing glial scarring. Our findings introduce a safe and effective method for treating central nervous system injuries, marking a significant advancement in regenerative neuroscience.

Osteopontine-derived functional fragments coupled to RADA16 self-assembled peptide hydrogels promotes bone and vascular regeneration in vivo

Biomaterial scaffolds have been widely used in tissue engineering. A functionalized self-assembled peptide scaffold named RADA16-OPD was designed by linking the short functional motif of osteopontine (OPN)-derived functional fragments SVVYGLR (OPD) to the C-terminus of the self-assembled peptide RADA16. Atomic force microscopy (AFM) was used to analyze the self-assembling peptide’s structural composition. The live/dead staining results showed that RADA16-OPD is not toxic to rASC. After creating a rat skull defect model artificially, micro-CT results revealed that the defect area treated with RADA16-OPD hydrogel had higher bone volume/total volume (BV/TV), a higher trabecular number (TB.N.), and higher bone density (BMD) at different treatment time points. Histological evaluation found that there was more new bone and mature collagen production in the RADA16-OPD group. Meanwhile, the RADA16-OPD group had higher expression of alkaline phosphatase (ALP) and osteocalcin (OCN) than the other two groups. Additionally, immunofluorescence revealed that the RADA16-OPD group had higher levels of platelet/endothelial cell adhesion molecule 1 (CD31) expression than the other two groups. It demonstrated the potential for clinical use of the RADA16-OPD peptide scaffold by promoting bone regeneration and blood vessel development in vivo.

Applications of self-assembled peptide hydrogels in anti-tumor therapy

Peptides are a class of active substances composed of a variety of amino acids with special physiological functions.

Biological activity of self-assembled peptide hydrogel scaffold RADA-RGD and its experimental study of BMP-2 release in vitro

A novel self-assembled peptide hydrogel scaffold RADA-RGD+BMP-2 was designed and prepared by adding RGD functional motifs to the amino acid sequence of RADA16. Transmission electron microscopy and scanning electron microscopy were used to examine the physicochemical properties of hydrogel scaffolds. To analyze the controlled release of BMP-2 when incorporated into RADA-RGD. Cells were cultivated in different extracellular matrix environments, where BMP-2 levels were assessed using ELISA, and cumulative release rates and release profiles were plotted. The biological activity and biosafety of growth factor-loaded polypeptides were evaluated using CCK-8 assay and live/dead staining. ALP staining, alizarin red staining, and quantitative mineralization assays were used to evaluate the contribution of growth factor peptides to in vitro mineralization. The in vivo ability of long-factor polypeptides to promote bone differentiation was evaluated using HE staining, Masson staining, and micro-CT. The results showed that RADA-RGD+BMP-2 was superior in stimulating cell proliferation, adhesion, and bone formation compared to RADA16-RGD. RADA-RGD demonstrated excellent biocompatibility and effective control over the release of BMP-2. These findings offer a potentially effective strategy for using self-assembled peptides to promote osteogenesis and regulate protein release.

Mesenchymal stem cells aligned and stretched in self-assembling peptide hydrogels

The presented research highlights a novel approach using fmoc-protected peptide hydrogels for the encapsulation and stretching of mesenchymal stem cells (MSCs). This study utilized a custom mechanical stretching device with a PDMS chamber to stretch human MSCs encapsulated in Fmoc hydrogels. The study assessed the influence of various solvents on the self-assembly and mechanical properties of the hydrogels, and MSC viability and alignment. Particularly we focused on fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF) prepared in dimethyl sulfoxide (DMSO), hexafluoro-2-propanol (HFP), and deionized water (DiH2O).Through molecular self-assembly of the peptide sequence into β-sheets connected by π-π aromatic stacking of F–F groups, the peptide hydrogel was found to form a stiff, hydrated gel with nanofiber morphology and a compressive modulus ranging from 174 to 277 Pa. Therefore, this hydrogel can mimic certain critical features of the extracellular matrix and collagen. Evaluations of MSCs cultured on the peptide hydrogels, including viability, morphology, and alignment assessments using various staining techniques, demonstrated that 3D-cultured MSCs in Fmoc-FF/HFP and Fmoc-FF/DMSO, followed by mechanical stretching, exhibited elongated morphology with distinct microfilament fibers compared to the control cells, which maintained a round and spherical F-actin shape. Notably, peptide gels with a concentration of 5 mM maintained 100 % MSC viability.The findings indicate the potential and specific conditions for successful cell encapsulation and alignment within peptide hydrogels, highlighting a promising tissue engineering platform through the encapsulation of MSCs in peptide nanofibers followed by a stretching process. By enhancing our understanding of MSC-peptide hydrogel interactions, this research contributes to the development of biomaterials tailored for regenerative medicine.

A novel octa-arginine-modified injectable self-assembling peptide hydrogel for multidrug-resistant cancer therapy

Surgery combined with systemic chemotherapy is currently the main modality of cancer treatment. However, the development of cancer multidrug resistance and inevitable surgical residual lesions lead to high rates of cancer recurrence and mortality. Meanwhile, systemic drug toxic side effects and surgical bleeding complications seriously reduce the quality of life of patients. To avoid cancer multidrug resistance and comprehensively optimize cancer treatment, this work provides a novel injectable cell penetrating peptide octa-arginine (R8)-modified RADA16 (RR) self-assembling peptide nanofiber hydrogel as an anticancer drug carrier for multidrug-resistant cancer therapy. In RR hydrogel, highly compatible RADA16 functions as the β-sheet-based self-assembling backbone which tightly adheres to cancer tissue, prevents postoperative bleeding, and sustainedly releases anticancer drugs for long-term effects. The introduced R8 motifs endow RR hydrogel with the capacity to selectively kill cancer cells and reverse cancer multidrug resistance, which minimally impact normal tissue cells. Specifically, R8 motifs on the hydrogel scaffold selectively interfere with cancer cell membranes, increase drug uptake and penetration into cancer cells and tissues by enhancing multiple internalization pathways, and reduce drug efflux by inhibiting P-gp and BCRP multidrug-resistant transporters. Therefore, this study provides a multifunctional hydrogel material with strong potential for multidrug-resistant cancer clinical translation.

Evaluation of a Peptide Hydrogel as a Chondro-Instructive Three-Dimensional Microenvironment.

Articular cartilage injuries are inherently irreversible, even with the advancement in current therapeutic options. Alternative approaches, such as the use of mesenchymal stem/stromal cells (MSCs) and tissue engineering techniques, have gained prominence. MSCs represent an ideal source of cells due to their low immunogenicity, paracrine activity, and ability to differentiate. Among biomaterials, self-assembling peptide hydrogels (SAPH) are interesting given their characteristics such as good biocompatibility and tunable properties. Herein we associate human adipose-derived stem cells (hASCs) with a commercial SAPH, Puramatrix™, to evaluate how this three-dimensional microenvironment affects cell behavior and its ability to undergo chondrogenic differentiation. We demonstrate that the Puramatrix™ hydrogel comprises a highly porous matrix permissible for hASC adhesion and in vitro expansion. The morphology and cell growth dynamics of hASCs were affected when cultured on the hydrogel but had minimal alteration in their immunophenotype. Interestingly, hASCs spontaneously formed cell aggregates throughout culturing. Analysis of glycosaminoglycan production and gene expression revealed a noteworthy and donor-dependent trend suggesting that Puramatrix™ hydrogel may have a natural capacity to support the chondrogenic differentiation of hASCs. Altogether, the results provide a more comprehensive understanding of the potential applications and limitations of the Puramatrix™ hydrogel in developing functional cartilage tissue constructs.

Selectively Positioned Catechol Moiety Supports Ultrashort Self-Assembling Peptide Hydrogel Adhesion for Coral Restoration.

Coral reef survival is threatened globally. One way to restore this delicate ecosystem is to enhance coral growth by the controlled propagation of coral fragments. To be sustainable, this technique requires the use of biocompatible underwater adhesives. Hydrogels based on rationally designed ultrashort self-assembling peptides (USP) are of great interest for various biological and environmental applications, due to their biocompatibility and tunable mechanical properties. Implementing superior adhesion properties to the USP hydrogel compounds is crucial in both water and high ionic strength solutions and is relevant in medical and marine environmental applications such as coral regeneration. Some marine animals secrete large quantities of the aminoacids dopa and lysine to enhance their adhesion to wet surfaces. Therefore, the addition of catechol moieties to the USP sequence containing lysine (IIZK) should improve the adhesive properties of USP hydrogels. However, it is challenging to place the catechol moiety (Do) within the USP sequence at an optimal position without compromising the hydrogel self-assembly process and mechanical properties. Here, we demonstrate that, among three USP hydrogels, DoIIZK is the least adhesive and that the adhesiveness of the IIZDoK hydrogel is compromised by its poor mechanical properties. The best adhesion outcome was achieved using the IIZKDo hydrogel, the only one to show equally sound adhesive and mechanical properties. A mechanistic understanding of this outcome is presented here. This property was confirmed by the successful gluing of coral fragments by means of IIZKDo hydrogel that are still thriving after more than three years since the deployment. The validated biocompatibility of this underwater hydrogel glue suggests that it could be advantageously implemented for other applications, such as surgical interventions.

Calming the Nerves via the Immune Instructive Physiochemical Properties of Self-Assembling Peptide Hydrogels.

Current therapies for the devastating damage caused by traumatic brain injuries (TBI) are limited. This is in part due to poor drug efficacy to modulate neuroinflammation, angiogenesis and/or promoting neuroprotection and is the combined result of challenges in getting drugs across the blood brain barrier, in a targeted approach. The negative impact of the injured extracellular matrix (ECM) has been identified as a factor in restricting post-injury plasticity of residual neurons and is shown to reduce the functional integration of grafted cells. Therefore, new strategies are needed to manipulate the extracellular environment at the subacute phase to enhance brain regeneration. In this review, potential strategies are to be discussed for the treatment of TBI by using self-assembling peptide (SAP) hydrogels, fabricated via the rational design of supramolecular peptide scaffolds, as an artificial ECM which under the appropriate conditions yields a supramolecular hydrogel. Sequence selection of the peptides allows the tuning of these hydrogels' physical and biochemical properties such as charge, hydrophobicity, cell adhesiveness, stiffness, factor presentation, degradation profile and responsiveness to (external) stimuli. This review aims to facilitate the development of more intelligent biomaterials in the future to satisfy the parameters, requirements, and opportunities for the effective treatment of TBI.