Nassir Mokarram

A Perspective on Immunomodulation and Tissue Repair

An immune response involves the action of all types of macrophages, classically activated subtype (M1) in the early inflammatory phase and regulatory and wound-healing subtypes (M2) in the resolution phase. The remarkable plasticity of macrophages makes them an interesting target in the context of immunomodulation. Here, we reviewed the current state of understanding regarding the role that different phenotypes of macrophages and monocytes play following injury and during the course of remodeling in different tissue types. Moreover, we explored recent designs of macrophage modulatory biomaterials for tissue engineering and regenerative medicine applications.

Novel high-performance nanohybrid polyelectrolyte membranes based on bio-functionalized montmorillonite for fuel cell applications.

This study is concerned with electrochemical investigation of novel high-performance proton exchange membranes based on bio-functionalized montmorillonite and Nafion. It was found that the incorporation of 2 wt% BMMT into Nafion polyelectrolyte matrix results in significantly improved methanol-air fuel cell efficiency of 30% compared to 14% for Nafion(R)117, and about 23-times higher membrane selectivity.

Overcoming Endogenous Constraints on Neuronal Regeneration

One of the grand challenges in neuroengineering is to stimulate regeneration after central nervous system (CNS) or peripheral nervous system (PNS) injury to restore function. The state of the art today is that PNS injuries heal to a limited extent, whereas CNS injuries are largely intractable to regeneration. In this context, we examine the underlying biochemical and cellular constraints on endogenous healing of neural tissues. Identification and characterization of endogenous “rate-limiting” processes that constrain regeneration would allow one to craft solutions to overcome critical impediments for accelerated healing. It is increasingly evident that biochemical pathways triggered by the nature and duration of injury-triggered inflammatory response may determine the endogenous constraints and subsequently determine regenerative fate. In this paper, critical endogenous constraints of PNS and CNS regeneration are identified, and the effects of modulating the phenotypes of immune cells on neuronal regeneration are discussed.

A microfluidic approach to synthesizing high-performance microfibers with tunable anhydrous proton conductivity

Here, we demonstrate a new approach for the synthesis of ion exchange microfibers with finely tuned anhydrous conductivity. This work presents microfluidics as a system to control the size and phosphoric acid (PA) doping level of the polybenzimidazole (PBI) microfibers. It has been shown that the PA doping level can be controlled by varying the flow ratios in the microfluidic channel. The diameter of the microfibers increased with extending mixing time, whereas the doping level decreased with increasing flow ratio. The highest doping level, 16, was achieved at the flow ratio of 0.175. The anhydrous proton conductivity of the microfibers was found to be adjustable between 0.01 and 0.1 S cm(-1) at 160 °C, which is considerably higher than for conventionally doped PBI cast membranes (0.004 S cm(-1)). Furthermore, molecular dynamic simulation of proton conduction through the microfibers at different doping levels was in good agreement with the experimental results. These results demonstrate the potential of the microfluidic technique to precisely tune the physicochemical properties of PBI microfibers for various electrochemical applications such as hydrogen sensors, fuel cells as well as artificial muscles.

Cellulose nanowhiskers to regulate the microstructure of perfluorosulfonate ionomers for high-performance fuel cells

Cellulose whiskers (CWs) were explored as effective nanostructures to manipulate the microstructure of Nafion® membranes for high-performance fuel cell applications. Electrochemical impedance measurements revealed that not only the proton conductivity of the nanocomposite membranes comprising 5 wt% CWs was remarkably increased, but the higher conductivity was also retained at higher temperatures (>100 °C). Moreover, it was found that the inclusion of CWs into a Nafion® matrix provides considerably suppressed methanol permeability. The direct methanol–air single fuel cell test using 5 M methanol solution at 70 °C showed a higher maximum power density of 91 mW cm−2 for the nanocomposite membrane, compared to 28 and 47 mW cm−2 for unmodified Nafion®. Hence, CWs could be considered as effective and elegant nanostructures to regulate the ionic microstructure and alleviate critical drawbacks of Nafion membranes for commercial direct methanol fuel cell applications.

Immunoengineering nerve repair

Significance Annually, more than 250,000 Americans suffer from a peripheral nerve injury, which results in a loss of function and a compromised quality of life. The current clinical gold standard to bridge long, nonhealing nerve gaps, the autograft, has several drawbacks. Therefore, there is a clear and urgent unmet clinical need for an alternative approach that can match or exceed autograft performance. Here we investigated the regenerative effect of fractalkine, a chemokine that preferentially recruits reparative monocytes in the synthetic nerve conduit. Our method of bridging gaps enhanced axonal regeneration and muscle reinnervation and showed results comparable to those observed in autografts. Injuries to the peripheral nervous system are major sources of disability and often result in painful neuropathies or the impairment of muscle movement and/or normal sensations. For gaps smaller than 10 mm in rodents, nearly normal functional recovery can be achieved; for longer gaps, however, there are challenges that have remained insurmountable. The current clinical gold standard used to bridge long, nonhealing nerve gaps, the autologous nerve graft (autograft), has several drawbacks. Despite best efforts, engineering an alternative “nerve bridge” for peripheral nerve repair remains elusive; hence, there is a compelling need to design new approaches that match or exceed the performance of autografts across critically sized nerve gaps. Here an immunomodulatory approach to stimulating nerve repair in a nerve-guidance scaffold was used to explore the regenerative effect of reparative monocyte recruitment. Early modulation of the immune environment at the injury site via fractalkine delivery resulted in a dramatic increase in regeneration as evident from histological and electrophysiological analyses. This study suggests that biasing the infiltrating inflammatory/immune cellular milieu after injury toward a proregenerative population creates a permissive environment for repair. This approach is a shift from the current modes of clinical and laboratory methods for nerve repair, which potentially opens an alternative paradigm to stimulate endogenous peripheral nerve repair.

Engineering challenges for brain tumor immunotherapy

ABSTRACT Malignant brain tumors represent one of the most devastating forms of cancer with abject survival rates that have not changed in the past 60 years. This is partly because the brain is a critical organ, and poses unique anatomical, physiological, and immunological barriers. The unique interplay of these barriers also provides an opportunity for creative engineering solutions. Cancer immunotherapy, a means of harnessing the host immune system for anti‐tumor efficacy, is becoming a standard approach for treating many cancers. However, its use in brain tumors is not widespread. This review discusses the current approaches, and hurdles to these approaches in treating brain tumors, with a focus on immunotherapies. We identify critical barriers to immunoengineering brain tumor therapies and discuss possible solutions to these challenges. Graphical abstract Figure. No Caption available.

Bacterial Carriers for Glioblastoma Therapy

Treatment of aggressive glioblastoma brain tumors is challenging, largely due to diffusion barriers preventing efficient drug dosing to tumors. To overcome these barriers, bacterial carriers that are actively motile and programmed to migrate and localize to tumor zones were designed. These carriers can induce apoptosis via hypoxia-controlled expression of a tumor suppressor protein p53 and a pro-apoptotic drug, Azurin. In a xenograft model of human glioblastoma in rats, bacterial carrier therapy conferred a significant survival benefit with 19% overall long-term survival of >100 days in treated animals relative to a median survival of 26 days in control untreated animals. Histological and proteomic analyses were performed to elucidate the safety and efficacy of these carriers, showing an absence of systemic toxicity and a restored neural environment in treated responders. In the treated non-responders, proteomic analysis revealed competing mechanisms of pro-apoptotic and drug-resistant activity. This bacterial carrier opens a versatile avenue to overcome diffusion barriers in glioblastoma by virtue of its active motility in extracellular space and can lead to tailored therapies via tumor-specific expression of tumoricidal proteins.

Noninvasive Imaging of Peripheral Nerves

Recent developments in the field of peripheral nerve imaging extend the capabilities of imaging modalities to assist in the diagnosis and treatment of patients with peripheral nerve maladies. Methods such as magnetic resonance imaging (MRI) and its derivative diffusion tensor imaging (DTI), ultrasound (US) and positron emission tomography (PET) are capable of assessing nerve structure and function following injury and relating the state of the nerve to electrophysiological and histological analysis. Of the imaging methods surveyed here, each offered unique and interesting advantages related to the field. MRI offered the opportunity to visualize immune activity on the injured nerve throughout the course of the regeneration process, and DTI offered numerical characterization of the injury and the ability to develop statistical bases for diagnosing injury. US extends imaging to the treatment phase by enabling more precise analgesic applications following surgery, and PET represents a novel method of assessing nerve injury through analysis of relative metabolism rates in injured and healthy tissue. Exciting new possibilities to enhance and extend the abilities of imaging methods are also discussed, including innovative contrast agents, some of which enable multimodal imaging approaches and present opportunities for treatment application.