Biology subjects

Enam, S. F.

Publications and source records attributed to Enam, S. F..

4 recordsLinked to original sources

bioRxiv2024

Finite element analysis of a neural implant for cytostatic hypothermia and a novel heat management system

The treatment of glioblastoma (GBM) presents significant challenges, with median survival rates remaining low despite standard-of-care therapies. This study expands upon the findings of a novel approach to managing GBM, namely cytostatic hypothermia, through the computational evaluation of a fully implantable system. Our proposed system utilizes a multi-probe array and a novel artificial internal circulation system (AICS) to achieve homogeneous cooling within the brain without overheating any portion of the body. Finite-element modeling was employed to simulate bioheat transfer and fluid dynamics. Our results indicate that the multi-probe array can attain local tissue temperatures within the cytostatic range (20 to 28degC) while minimizing thermal gradients. The use of multiple narrow, thermally conductive probes enhances cooling uniformity with minimal tissue displacement. The revolutionary AICS provides a form of heat management that has not previously been attempted to the best of our knowledge. In this study, it successfully facilitates the transfer of heat from the intracranial region to the skin in the body. Future work will focus on device prototyping and validation through in vitro and in vivo studies in large animal models. These simulations suggest that the proposed intracranial cooling system makes cytostatic hypothermia a practicable approach against GBM. Furthermore, this approach to internal heat management may also open new avenues for treating neurological conditions through local and chronic hypothermia, extending beyond the short-duration (acute) cooling methods currently tested.

bioengineering↗

bioRxiv2021

DIY caging apparatus to facilitate chronic and continuous stimulation or recording in an awake rodent

Chronic stimulation of and recording from the brain and brain diseases can require expensive apparatus and tedious cycles of inducing rodents with anesthesia. To resolve this, we have designed and fabricated a low-cost ([~]$75 vs. $450) DIY rodent caging apparatus consisting of commercially available and 3D-printed components. This apparatus is customizable and can be used to rapidly prototype devices with large rodent sample sizes. Importantly, it enables continuous and chronic stimulation of and recording from the brains of awake and freely moving rodents. It also opens the possibilities of trying complex paradigms of treatment (continuous, intermittent, variable, and chronic). We have successfully used this caging apparatus for chronic intratumoral hypothermia treatment and are currently using it while advancing electrotactic therapies.

bioengineering↗

bioRxiv2021

Cytostatic hypothermia and its impact on glioblastoma and survival

Novel therapeutic approaches are needed for patients with glioblastoma (GBM) who otherwise have limited options. Here we studied and deployed non-freezing cytostatic hypothermia to stunt GBM growth. This contrasts with ablative, cryogenic hypothermia: a double-edged sword against tumors infiltrating otherwise healthy tissue. We investigated three grades of hypothermia in vitro and identified a cytostatic window of 20-25{degrees}C. For some glioma lines, 18 h/d of cytostatic hypothermia was sufficient to halt division in vitro. Cytostatic hypothermia induced cell cycle arrest, reduced metabolite production and consumption, and reduced inflammatory cytokine synthesis. Next, we fabricated an experimental device to test local cytostatic hypothermia in vivo in two rodent models of GBM: utilizing the rat F98 and the human U-87 MG lines. Hypothermia more than doubled the median survival of F98 bearing rats from 3.9 weeks to 9.7 weeks and two rats survived through 12 weeks. All U-87 MG bearing rats that successfully received cytostatic hypothermia survived their study period. Thus, this approach lengthened survival without chemical interventions. Unlike targeted therapeutics that are successful in preclinical models but fail in clinical trials, cytostatic hypothermia affects multiple cellular processes simultaneously. This, alongside reduced cellular division, suggests that opportunities for tumor evolution are reduced and the likelihood of translation to larger species may be more likely. In addition, based on our work, designs, and the literature, engineering a patient-centric device is tangible. Taken together, cytostatic hypothermia could be a novel approach to cancer therapy and eventually serve a valuable role to patients with GBM. One Sentence SummaryHypothermia influences multiple cellular pathways, can be a safe and effective approach to halt glioblastoma growth, and holds translational promise.

bioengineering↗

bioRxiv2020

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells

Appropriately modulating inflammation after traumatic brain injury (TBI) may prevent disabilities for the millions of those inflicted annually. In TBI, cellular mediators of inflammation, including macrophages and microglia, possess a range of phenotypes relevant for an immunomodulatory therapeutic approach. It is thought that early phenotypic modulation of these cells will have a cascading healing effect. In fact, an anti-inflammatory, "M2-like" macrophage phenotype after TBI has been associated with neurogenesis, axonal regeneration, and improved white matter integrity. There already exists clinical trials seeking an M2-like bias through mesenchymal stem/stromal cells (MSCs). However, MSCs do not endogenously synthesize key signals that induce robust M2-like phenotypes such as Interleukin-4 (IL-4). To enrich M2-like macrophages in a clinically relevant manner, we augmented MSCs to transiently express IL-4 via synthetic IL-4 mRNA. We observed that these IL-4 expressing MSCs indeed induce a robust M2-like macrophage phenotype and promote anti-inflammatory gene expression in a modified TBI model of closed head injury. However, here we demonstrate that acute enrichment of M2-like macrophages did not translate to improved functional or histological outcomes. This suggests that an acute enrichment of M2-like macrophages cannot solely orchestrate the neurogenesis, axonal regeneration, and improved WMI after diffuse TBI. To further understand whether dysfunctional pathways underlie the lack of therapeutic effect, we report transcriptomic analysis of injured and treated brains. Through this, we discovered that inflammation persists in spite of acute enrichment of M2-like macrophages in the brain. Last, we comment on our modified TBI model, behavioral studies, and propose that IL-4 expressing MSCs may also have relevance in other cavitary diseases or in improving biomaterial integration into tissues.

neuroscience↗