ConspectusMultidomain peptides (MDPs) are a class of self-assembling peptides that are organized in a β-sheet motif, resulting in a nanofibrous architecture. This structure is stabilized by hydrophobic packing in the fiber core and a hydrogen-bonding network down the fiber long axis. Under easily controllable conditions, regulated by electrostatic interactions between the peptides and the pH and salt composition of the solvent, the nanofiber length can be dramatically extended, resulting in fiber entanglement and hydrogel formation. One of the chief strengths of this supramolecular material is that the design criteria governing its structure and assembly are robust and permit a wide range of modifications without disruption. This allows the MDPs to be tailored to suit a wide range of applications, particularly in biomedical engineering. For example, delivery of small molecules, proteins, and cells is easily achievable. These materials can be trapped within the matrices of the hydrogel or trapped within the hydrophobic core of the nanofiber, depending on the cargo and the design of the MDP. Interactions between the nanofibers and their cargo can be tailored to alter the release profile, and in the most sophisticated cases, different cargos can be released in a cascading time-dependent fashion. The MDP hydrogel and its cargo can be targeted to specific locations, as the thixotropic nature of the hydrogel allows it to be easily aspirated into a syringe and then delivered from a narrow-bore needle. The sequence of amino acids making up the MDP can also be modified to permit cross-linking or enzymatic degradation. Selection of sequences with or without these modifications allows one to control the rate of degradation in vivo from as rapidly as 1 week to well over 6 weeks as the MDP nanofibers are degraded to their amino acid components. MDP sequences can also be modified to add biomimetic sequences derived from growth factors and other signaling proteins. These chemical signals are displayed at a very high density on the fibers’ surface, where they contribute to the modification of cellular behavior. We have used this approach to drive blood vessel formation, which is critical for tissue regeneration generally and more specifically for the treatment of diseases related to poor blood flow. MDPs represent an ideal case of bottom-up design where control of chemical structure leads to control of self-assembly and nanostructure and thereby control of material properties that collectively can control biological function.

For a proangiogenic therapy to be successful, it must promote the development of mature vasculature for rapid reperfusion of ischemic tissue. Whole growth factor, stem cell, and gene therapies have yet to achieve the clinical success needed to become FDA-approved revascularization therapies. Herein, we characterize a biodegradable peptide-based scaffold engineered to mimic VEGF and self-assemble into a nanofibrous, thixotropic hydrogel, SLanc. We found that this injectable hydrogel was rapidly infiltrated by host cells and could be degraded while promoting the generation of neovessels. In mice with induced hind limb ischemia, this synthetic peptide scaffold promoted angiogenesis and ischemic tissue recovery, as shown by Doppler-quantified limb perfusion and a treadmill endurance test. Thirteen-month-old mice showed significant recovery within 7 days of treatment. Biodistribution studies in healthy mice showed that the hydrogel is safe when administered intramuscularly, subcutaneously, or intravenously. These preclinical studies help establish the efficacy of this treatment for peripheral artery disease due to diminished microvascular perfusion, a necessary step before clinical translation. This peptide-based approach eliminates the need for cell transplantation or viral gene transfection (therapies currently being assessed in clinical trials) and could be a more effective regenerative medicine approach to microvascular tissue engineering.

The design of materials for regenerative medicine has focused on delivery of small molecule drugs, proteins, and cells to help accelerate healing. Additionally, biomaterials have been designed with covalently attached mimics of growth factors, cytokines, or key extracellular matrix components allowing the biomaterial itself to drive biological response. While the approach may vary, the goal of biomaterial design has often centered on promoting either cellular infiltration, degradation, vascularization, or innervation of the scaffold. Numerous successful studies have utilized this complex, multicomponent approach; however, we demonstrate here that a simple nanofibrous peptide hydrogel unexpectedly and innately promotes all of these regenerative responses when subcutaneously implanted into the dorsal tissue of healthy rats. Despite containing no small molecule drugs, cells, proteins or protein mimics, the innate response to this material results in rapid cellular infiltration, production of a wide range of cytokines and growth factors by the infiltrating cells, and remodeling of the synthetic material to a natural collagen-containing ECM. During the remodeling process, a strong angiogenic response and an unprecedented degree of innervation is observed. Collectively, this simple peptide-based material provides an ideal foundational system for a variety of bioregenerative approaches.

In vivo, multidomain peptide (MDP) hydrogels undergo rapid cell infiltration and elicit a mild inflammatory response which promotes angiogenesis. Over time, the nanofibers are degraded and a natural collagen-based extracellular matrix is produced remodeling the artificial material into natural tissue. These properties make MDPs particularly well suited for applications in regeneration. In this work, we test the regenerative potential of MDP hydrogels in a diabetic wound healing model. When applied to full-thickness dermal wounds in genetically diabetic mice, the MDP hydrogel resulted in significantly accelerated wound healing compared to a clinically used hydrogel, as well as a control buffer. Treatment with the MDP hydrogel resulted in wound closure in 14 days, formation of thick granulation tissue including dense vascularization, innervation, and hair follicle regeneration. This suggests the MDP hydrogel could be an attractive choice for treatment of wounds in diabetic patients.

In dentistry, the maintenance of a vital dental pulp is of paramount importance, as teeth devitalized by root canal treatment may become more brittle and prone to structural failure over time. Advanced carious lesions can irreversibly damage the dental pulp by propagating a sustained inflammatory response throughout the tissue. While the inflammatory response initially drives tissue repair, sustained inflammation has an enormously destructive effect on the vital pulp, eventually leading to total necrosis of the tissue and necessitating its removal. The implications of tooth devitalization have driven significant interest in the development of bioactive materials that facilitate the regeneration of damaged pulp tissues by harnessing the capacity of the dental pulp for self-repair. In considering the process by which pulpitis drives tissue destruction, it is clear that an important step in supporting the regeneration of pulpal tissues is the attenuation of inflammation. Macrophages, key mediators of the immune response, may play a critical role in the resolution of pulpitis due to their ability to switch to a pro-resolution phenotype. This process can be driven by the resolvins, a family of molecules derived from fatty acids that show great promise as therapeutic agents. In this review, we outline the importance of preserving the capacity of the dental pulp to self-repair through the rapid attenuation of inflammation. Potential treatment modalities, such as shifting macrophages to a pro-resolving phenotype with resolvins are described, and a range of materials known to support the regeneration of dental pulp are presented.