N-Cadherin Mimetic Peptide Nanofiber System Induces Chondrogenic Differentiation of Mesenchymal Stem Cells.

Cadherins are vital for cell-to-cell interactions during tissue growth, migration, and differentiation processes. Both biophysical and biochemical inputs are generated upon cell-to-cell adhesions, which determine the fate of the mesenchymal stem cells (MSCs). The effect of cadherin interactions on the MSC differentiation still remains elusive. Here we combined the N-Cadherin mimetic peptide (HAV-PA) with the self-assembling E-PA and the resultant N-cadherin mimetic peptide nanofibers promoted chondrogenic differentiation of MSCs in conjunction with chondrogenic factors as a synthetic extracellular matrix system. Self-assembly of the precursor peptide amphiphile molecules HAV-PA and E-PA enable the organization of HAV peptide residues in close proximity to the cell interaction site, forming a supramolecular N-cadherin-like system. These bioactive peptide nanofibers not only promoted viability and enhanced adhesion of MSCs but also augmented the expression of cartilage specific matrix components compared to the nonbioactive control nanofibers. Overall, the N-cadherin mimetic peptide nanofiber system facilitated MSC commitment into the chondrogenic lineage presenting an alternative bioactive platform for stem-cell-based cartilage regeneration.

Nanoengineered Sprayable Therapy for Treating Myocardial Infarction.

We report the development, as well as the in vitro and in vivo testing, of a sprayable nanotherapeutic that uses surface engineered custom-designed multiarmed peptide grafted nanogold for on-the-spot coating of an infarcted myocardial surface. When applied to mouse hearts, 1 week after infarction, the spray-on treatment resulted in an increase in cardiac function (2.4-fold), muscle contractility, and myocardial electrical conductivity. The applied nanogold remained at the treatment site 28 days postapplication with no off-target organ infiltration. Further, the infarct size in the mice that received treatment was found to be <10% of the total left ventricle area, while the number of blood vessels, prohealing macrophages, and cardiomyocytes increased to levels comparable to that of a healthy animal. Our cumulative data suggest that the therapeutic action of our spray-on nanotherapeutic is highly effective, and in practice, its application is simpler than other regenerative approaches for treating an infarcted heart.

Riboflavin Surface Modification of Poly(vinyl chloride) for Light-Triggered Control of Bacterial Biofilm and Virus Inactivation.

Poly(vinyl chloride) (PVC) is the most used biomedical polymer worldwide. PVC is a stable and chemically inert polymer. However, microorganisms can colonize PVC producing biomedical device-associated infections. While surface modifications of PVC can help improve the antimicrobial and antiviral properties, the chemically inert nature of PVC makes those modifications challenging and potentially toxic. In this work, we modified the PVC surface using a derivative riboflavin molecule that was chemically tethered to a plasma-treated PVC surface. Upon a low dosage of blue light, the riboflavin tethered to the PVC surface became photochemically activated, allowing for Pseudomonas aeruginosa bacterial biofilm and lentiviral in situ eradication.

Delivering More of an Injectable Human Recombinant Collagen III Hydrogel Does Not Improve Its Therapeutic Efficacy for Treating Myocardial Infarction.

Injectable hydrogels are a promising method to enhance repair in the heart after myocardial infarction (MI). However, few studies have compared different strategies for the application of biomaterial treatments. In this study, we use a clinically relevant mouse MI model to assess the therapeutic efficacy of different treatment protocols for intramyocardial injection of a recombinant human collagen III (rHCIII) thermoresponsive hydrogel. Comparing a single hydrogel injection at an early time point (3 h) versus injections at multiple time points (3 h, 1 week, and 2 weeks) post-MI revealed that the single injection group led to superior cardiac function, reduced scar size and inflammation, and increased vascularization. Omitting the 3 h time point and delivering the hydrogel at 1 and 2 weeks post-MI led to poorer cardiac function. The positive effects of the single time point injection (3 h) on scar size and vascular density were lost when the hydrogel's collagen concentration was increased from 1% to 2%, and it did not confer any additional functional improvement. This study shows that early treatment with a rHCIII hydrogel can improve cardiac function post-MI but that injecting more rHCIII (by increased concentration or more over time) can reduce its efficacy, thus highlighting the importance of investigating optimal treatment strategies of biomaterial therapy for MI.

Collagen-Based Microcapsules As Therapeutic Materials for Stem Cell Therapies in Infarcted Myocardium.

As cell therapies emerged, it was quickly realized that pro-regenerative cells directly injected into injured tissue struggled within the inflammatory microenvironment. By using microencapsulation, i.e., encapsulating cells within polymeric biomaterials, they are henceforth protected from the harmful extracellular cues, while still being able to receive oxygen and nutrients and release secreted factors. Previous work showed that stem cells encapsulated within a biologically inert material (agarose) were able to significantly improve the function of the infarcted mouse heart. With the aim of using more bioresponsive microcapsules, we sought to develop an enzymatically degradable, type I collagen-based microcapsule for the intramyocardial delivery of bone marrow-derived mesenchymal stromal cells in a murine model of myocardial infarction.

Multifunctional Nano and Collagen-Based Therapeutic Materials for Skin Repair.

A novel strategy is needed for treating nonhealing wounds, which is able to simultaneously eradicate pathogenic bacteria and promote tissue regeneration. This would improve patient outcome and reduce the number of lower limb amputations. In this work, we present a multifunctional therapeutic approach able to control bacterial infections, provide a protective barrier to a full-thickness wound, and improve wound healing in a clinically relevant animal model. Our approach uses a nanoengineered antimicrobial nanoparticle for creating a sprayable layer onto the wound bed that prevents bacterial proliferation and also eradicates preformed biofilms. As a protective barrier for the wound, we developed a thermoresponsive collagen-based matrix that has prohealing properties and is able to fill wounds independent of their geometries. Our results indicate that using a combination of the matrix with full-thickness microscopic skin tissue columns synergistically contributed to faster and superior skin regeneration in a nonhealing wound model in diabetic mice.

Protective therapeutic effects of peptide nanofiber and hyaluronic acid hybrid membrane in in vivo osteoarthritis model.

Osteoarthritis (OA) is a condition where tissue function is lost through a combination of secondary inflammation and deterioration in articular cartilage. One of the most common causes of OA is age-related tissue impairment because of wear and tear due to mechanical erosion. Hyaluronic acid-based viscoelastic supplements have been widely used for the treatment of knee injuries. However, the current formulations of hyaluronic acid are unable to provide efficient healing and recovery. Here, a nanofiber-hyaluronic acid membrane system that was prepared by using a quarter of the concentration of commercially available hyaluronic acid supplement, Hyalgan®, was used for the treatment of an osteoarthritis model, and Synvisc®, which is another commercially available hyaluronic acid containing viscoelastic supplement, was used as a control. The results show that this system provides efficient protection of arthritic cartilage tissue through the preservation of cartilage morphology with reduced osteophyte formation, protection of the subchondral region from deterioration, and maintenance of cartilage specific matrix proteins in vivo. In addition, the hybrid nanofiber membrane enabled chondrocyte encapsulation and provided a suitable culturing environment for stem cell growth in vitro. Overall, our results suggest that this hybrid nanofibrous scaffold provides a potential platform the treatment of OA. STATEMENT OF SIGNIFICANCE: Osteoarthritis is a debilitating joint disease affecting millions of people worldwide. It occurs especially in knees due to aging, sport injuries or obesity. Although hyaluronic acid-based viscoelastic supplements are widely used, there is still no effective treatment method for osteoarthritis, which necessitates surgical operation as an only choice for severe cases. Therefore, there is an urgent need for efficient therapeutics. In this study, a nanofiber-HA membrane system was developed for the efficient protection of arthritic cartilage tissue from degeneration. This hybrid nanofiber system provided superior therapeutic activity at a relatively lower concentration of hyaluronic acid than Hyalgan® and Synvisc® gels, which are currently used in clinics. This work demonstrates for the first time that this hybrid nanofiber membrane scaffold can be utilized as a potential candidate for osteoarthritis treatment.

Laminin mimetic peptide nanofibers regenerate acute muscle defect.

Skeletal muscle cells are terminally differentiated and require the activation of muscle progenitor (satellite) cells for their regeneration. There is a clinical need for faster and more efficient treatment methods for acute muscle injuries, and the stimulation of satellite cell proliferation is promising in this context. In this study, we designed and synthesized a laminin-mimetic bioactive peptide (LM/E-PA) system that is capable of accelerating satellite cell activation by emulating the structure and function of laminin, a major protein of the basal membrane of the skeletal muscle. The LM/E-PA nanofibers enhance myogenic differentiation in vitro and the clinical relevance of the laminin-mimetic bioactive scaffold system was demonstrated further by assessing its effect on the regeneration of acute muscle injury in a rat model. Laminin mimetic peptide nanofibers significantly promoted satellite cell activation in skeletal muscle and accelerated myofibrillar regeneration following acute muscle injury. In addition, the LM/E-PA scaffold treatment significantly reduced the time required for the structural and functional repair of skeletal muscle. This study represents one of the first examples of molecular- and tissue-level regeneration of skeletal muscle facilitated by bioactive peptide nanofibers following acute muscle injury. SIGNIFICANCE STATEMENT: Sports, heavy lifting and other strength-intensive tasks are ubiquitous in modern life and likely to cause acute skeletal muscle injury. Speeding up regeneration of skeletal muscle injuries would not only shorten the duration of recovery for the patient, but also support the general health and functionality of the repaired muscle tissue. In this work, we designed and synthesized a laminin-mimetic nanosystem to enhance muscle regeneration. We tested its activity in a rat tibialis anterior muscle by injecting the bioactive nanosystem. The evaluation of the regeneration and differentiation capacity of skeletal muscle suggested that the laminin-mimetic nanosystem enhances skeletal muscle regeneration and provides a suitable platform that is highly promising for the regeneration of acute muscle injuries. This work demonstrates for the first time that laminin-mimetic self-assembled peptide nanosystems facilitate myogenic differentiation in vivo without the need for additional treatment.