Search

Beta cell replacement has emerged as an attractive therapeutic alternative to traditional exogenous insulin administration for management of type 1 diabetes (T1D). Beta cells deliver insulin dynamically based on individual glycometabolic requirements, providing glycemic control while significantly reducing patient burden. Although transplantation into the portal circulation is clinically available, poor engraftment, low cell survival, and immune rejection have sparked investigation of alternative strategies for beta cell transplantation. In this review, we focus on current micro- and macroencapsulation technologies for beta cell transplantation and evaluate their advantages and challenges. Specifically, we comment on recent methods to ameliorate graft hypoxia including enhanced vascularization, reduction of pericapsular fibrotic overgrowth (PFO), and oxygen supplementation. We also discuss emerging beta cell-sourcing strategies to overcome donor shortage and provide insight into potential approaches to address outstanding challenges in the field., Competing Interests: Declaration of interests A.G. and J.P-M. are inventors of intellectual properties licensed by NanoGland, LLC., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Diabetes mellitus is an ever-increasing medical condition that currently suffers 1 of 11 adults who may have lifelong commitment with insulin injections. Cell-laden hydrogels releasing insulin may provide the ultimate means of correcting diabetes. Here, we provide insights of this cell-based approach including latest preclinical and clinical progress both from academia and industry., Area Covered: The present article focuses on reviewing latest advances in cell-laden hydrogels both from the technological and biological perspective. The most relevant clinical results including clinical trials are also discussed., Expert Opinion: Current progress in technological issues (stem cells, devices, biomaterials) have contributed cell encapsulation science to have a very relevant progress in the field of diabetes treatment.

Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults. This neurological disorder is characterized by focal seizures originating in the temporal lobe, often with secondary generalization. A variety of pharmacological treatments exist for patients suffering from focal seizures, but systemically administered drugs offer only symptomatic relief and frequently cause unwanted side effects. Moreover, available drugs are ineffective in one third of the epilepsy patients. Thus, developing more targeted and effective treatment strategies for focal seizures, originating from, e.g., the temporal lobe, is highly warranted. In order to deliver potential anti-epileptic agents directly into the seizure focus we used encapsulated cell biodelivery (ECB), a specific type of ex vivo gene therapy. Specifically, we asked whether unilateral delivery of glial cell line-derived neurotrophic factor (GDNF), exclusively into the epileptic focus, would suppress already established spontaneous recurrent seizures (SRS) in rats. Our results show that GDNF delivered by ECB devices unilaterally into the seizure focus in the hippocampus effectively decreases the number of SRS in epileptic rats. Thus, our study demonstrates that focal unilateral delivery of neurotrophic factors, such as GDNF, using ex vivo gene therapy based on ECB devices could be an effective anti-epileptic strategy providing a bases for the development of a novel, alternative, treatment for focal epilepsies.

Encapsulating, or immunoisolating, insulin-secreting cells within implantable, semipermeable membranes is an emerging treatment for type 1 diabetes. This approach can eliminate the need for immunosuppressive drug treatments to prevent transplant rejection and overcome the shortage of donor tissues by utilizing cells derived from allogeneic or xenogeneic sources. Encapsulation device designs are being optimized alongside the development of clinically viable, replenishable, insulin-producing stem cells, for the first time creating the possibility of widespread therapeutic use of this technology. Here, we highlight the status of the most advanced and widely explored implementations of cell encapsulation with an eye toward translating the potential of this technological approach to medical reality., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Huntington's disease (HD) is characterized by a significant loss of striatal neurons that project to the globus pallidus and substantia nigra, together with loss of cortical projection neurons in varying regions. Mutant huntingtin is suggested to drive the pathogenesis partially by downregulating corticostriatal brain-derived neurotrophic factor (BDNF) levels and signaling. Neurotrophic factors are endogenous peptides that promote the survival and maintenance of neurons. BDNF and other neurotrophic factors have shown neuroprotective benefits in various animal models of neurodegeneration, and are interesting candidates to protect the cell populations that are destined to die in HD. In an attempt to enhance the delivery of neurotrophic factors, several methods have been established to deliver long-term neurotrophic factor gene therapy to human target tissues. This chapter discusses two alternative approaches that have been shown to have potential to deliver neurotrophic factors as a neuroprotective gene therapy for HD. The methods are (1) ex vivo approach where encapsulated cells engineered to express neurotrophic factor are inserted into brain parenchyma or ventricle, and (2) in vivo viral vector therapy, in which viral vector is injected into desired brain area to express gene of interest in the host cells.

Treating many chronic diseases will require a tight, minute-to-minute regulation of therapeutic molecules that is currently not achievable with most pharmaceutical therapies. For these diseases, implantable living cellular systems may be able to provide unlimited drug delivery, enabling seamless matching of treatment duration with disease longevity. Cell encapsulation is an advanced technology that achieves this goal and represents a viable therapeutic option. The advanced state of the field has allowed researchers to inch forward into therapeutic domains previously untouchable because of the myriad disparate fields that intersect biomaterials and cells. Here, we discuss the next generation of clinical trials and potential approaches, 'smart' and responsive encapsulation systems, sophisticated and multifunctional devices, and novel imaging tools, together with the future challenges in the field., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Cancer vaccines are typically formulated for bolus injection and often produce short-lived immunostimulation resulting in poor temporal control over immune cell activation and weak oncolytic activity. One means of overcoming these limitations utilizes immunologically active biomaterial constructs. We previously reported that antigen-laden, macroporous PLG scaffolds induce potent dendritic cell (DC) and cytotoxic T-lymphocyte (CTL) responses via the controlled signaling of inflammatory cytokines, antigen and toll-like receptor agonists. In this study, we describe the kinetics of these responses and illustrate their fundamental relationship to potent tumor rejection when implanted subcutaneously in a mouse B16 model of melanoma. By explanting scaffolds from mice at times ranging from 1-7 d, a seamless relationship was observed between the production of controlled CTL responses, tumor growth and long-term survival in both prophylactic and therapeutic models. Scaffolds must be implanted for > 7 d to augment CTL responses via the prolonged presentation of tumor antigen, and the benefits included a notable regression of established tumors. Host DC infiltration into the porous material persisted for 12 days (peaking at day 5 ~1.4 x 10(6) cells), and a sharp attenuation in DC numbers coincided with peak CD8(+) CTL infiltration at day 12 (~8 x 10(5) cells). Importantly, these PLG systems enhanced DC numbers in the draining lymph node, resulting in increased CD(+) CTL subsets at days 10-16 of vaccination. These results indicate that material systems can finely control innate and adaptive immune cell responses to kill typically untreatable melanoma tumors and provide critical kinetic data for the design of vaccine carriers.

Vaccines are largely ineffective for patients with established cancer, as advanced disease requires potent and sustained activation of CD8(+) cytotoxic T lymphocytes (CTLs) to kill tumor cells and clear the disease. Recent studies have found that subsets of dendritic cells (DCs) specialize in antigen cross-presentation and in the production of cytokines, which regulate both CTLs and T regulatory (Treg) cells that shut down effector T cell responses. Here, we addressed the hypothesis that coordinated regulation of a DC network, and plasmacytoid DCs (pDCs) and CD8(+) DCs in particular, could enhance host immunity in mice. We used functionalized biomaterials incorporating various combinations of an inflammatory cytokine, immune danger signal, and tumor lysates to control the activation and localization of host DC populations in situ. The numbers of pDCs and CD8(+) DCs, and the endogenous production of interleukin-12, all correlated strongly with the magnitude of protective antitumor immunity and the generation of potent CD8(+) CTLs. Vaccination by this method maintained local and systemic CTL responses for extended periods while inhibiting FoxP3 Treg activity during antigen clearance, resulting in complete regression of distant and established melanoma tumors. The efficacy of this vaccine as a monotherapy against large invasive tumors may be a result of the local activity of pDCs and CD8(+) DCs induced by persistent danger and antigen signaling at the vaccine site. These results indicate that a critical pattern of DC subsets correlates with the evolution of therapeutic antitumor responses and provide a template for future vaccine design.

Leguminous plants (such as peas and soybeans) and rhizobial soil bacteria are symbiotic partners that communicate through molecular signaling pathways, resulting in the formation of nodules on legume roots and occasionally stems that house nitrogen-fixing bacteria. Nodule formation has been assumed to be exclusively initiated by the binding of bacterial, host-specific lipochito-oligosaccharidic Nod factors, encoded by the nodABC genes, to kinase-like receptors of the plant. Here we show by complete genome sequencing of two symbiotic, photosynthetic, Bradyrhizobium strains, BTAi1 and ORS278, that canonical nodABC genes and typical lipochito-oligosaccharidic Nod factors are not required for symbiosis in some legumes. Mutational analyses indicated that these unique rhizobia use an alternative pathway to initiate symbioses, where a purine derivative may play a key role in triggering nodule formation.

PMF is one of the major methods for protein identification using the MS technology. It is faster and cheaper than MS/MS. Although PMF does not differentiate trypsin-digested peptides of identical mass, which makes it less informative than MS/MS, current computational methods for PMF have the potential to improve its detection accuracy by better use of the information content in PMF spectra. We developed a number of new probability-based scoring functions for PMF protein identification based on the MOWSE algorithm. We considered a detailed distribution of matching masses in a protein database and peak intensity, as well as the likelihood of peptide matches to be close to each other in a protein sequence. Our computational methods are assessed and compared with other methods using PMF data of 52 gel spots of known protein standards. The comparison shows that our new scoring schemes have higher or comparable accuracies for protein identification in comparison to the existing methods. Our software is freely available upon request. The scoring functions can be easily incorporated into other proteomics software packages.

Cell replacement therapy has been widely suggested as a treatment for multiple diseases including motor neuron disease. A variety of donor cells have been tested for treatment including isolated preparations from bone marrow and embryonic spinal cord. Another cell source, Sertoli cells, have been successfully used in models of diabetes, Parkinson's disease and Huntington's disease. The ability of these cells to secrete cytoprotective proteins and their role as 'nurse cells' supporting the function of other cell types in the testes suggest their potential use as neuroprotective cells. The current study examines the ability of Sertoli cells injected into the parenchyma of the spinal cord to protect motor neurons in a mouse model for amyotrophic lateral sclerosis. Seventy transgenic mice expressing the mutant (G93A) human Cu-Zn superoxide dismutase (SOD1) received a unilateral spinal injection of Sertoli-enriched testicular cells into the L4-L5 ventral horn (1 x 10(5) cells total) prior to the onset of clinical symptoms. The animals were euthanized at the end stage of the disease. Histological and morphometric analyses of the transplant site were performed. A significant increase in the number of surviving ChAT positive motor neurons was found ipsilateral to the injection compared with contralateral and uninjected spinal cord. The ipsilateral increase in motor neuron density was dependent upon proximity to the injection site. Sections rostral or caudal to the injection site did not display a similar difference in motor neuron density. Implantation of a Sertoli-cell-enriched preparation has a significant neuroprotective benefit to vulnerable motor neurons in the SOD1 transgenic model. The therapeutic benefit may be the result of secreted neurotrophic factors present at a critical stage of motor neuron degeneration in this model.

Neurotrophic factors have the ability to protect and initiate growth of neurons. In the central nervous system, neurotrophic factors are neuroprotective in a wide range of disease states. Similarly, disease pathologies of the neurosensory retina respond favourably in animal models of retinitis pigmentosa, macular degeneration, glaucoma and others. With advances in drug delivery and cell therapy, an almost universal increase in efficacy is being realised. Now, repeated injections of neurotrophic factors are being replaced by controlled delivery of cell-mediated factor secretion, reducing the number of potential acute side effects. Tissue engineering strategies in conjunction with gene-modulated protein therapy or gene transfer are creating a unique treatment niche and are quickly gaining acclaim in the clinic. This review surveys the founding and current work on neurotrophic factors such as CNTF, BDNF, GDNF, LEDGF, PEDF and others. Ongoing clinical trials and successful preclinical studies are summarised as well.

Pancreatic islet transplantation into type 1 diabetic patients is currently being performed by intraportal infusion. This method, albeit reproducible, has some disadvantages including potential development of portal hypertension, hemorrhage, and an inability to retrieve or detect the transplanted tissue. Other transplant sites have been examined in animal models including the omentum, peritoneal cavity, and the spleen. A transplant site that has not been successful in supporting functional islet tissue transplantation in humans is the subcutaneous space due primarily to the lack of a well-defined vascular bed. This site has many favorable characteristics such as ease of access for transplantation and potential for removal of the transplanted tissue with a minimally invasive surgical procedure. This report addresses the evaluation of a subcutaneously placed device for the support of rat syngeneic islet transplantation in a streptozocin-induced diabetic model. The data generated support the use of this device for islet engraftment. In addition, beta cell function in this device compared favorably with the function of islets transplanted to the renal subcapsular space as well as islets within the native pancreas.

The efficacy of oral L-dopa becomes problematic with the progression of Parkinson's disease, due in large part to a lost ability to accommodate L-dopa's inherently poor pharmacokinetics. Pulmonary delivery represents a novel approach to reducing this problem. L-dopa was formulated into inhalable (Alkermes AIR) particles, and its pharmacokinetics and pharmacodynamics compared with those of an oral formulation. Pulmonary administration of L-dopa (2 mg) to rats resulted in a rapid elevation of plasma levels (C(max) = 4.8 +/- 1.10 microg/ml at 2 min), whereas oral administration of L-dopa produced a much delayed and lower C(max) (1.8 +/- 0.40 microg/ml at 30 min). In a rat model of Parkinson's disease (unilateral 6-hydroxydopamine lesion), the pulmonary formulation of L-dopa (0.5-2.0 mg) yielded more rapid and robust elevations in striatal L-dopa, dopamine, and dihydroxyphenylacetic acid levels, as well as 2.5 to 3.7 times as many c-fos-expressing striatal neurons. Moreover, motor function was significantly improved by 10 min after administration, with peak improvements occurring within 15 to 30 min. In contrast, considerably higher doses (6.8-10 mg) of orally administered L-dopa took over three times longer to produce similar effects. These results suggest that an inhalable formulation of l-dopa has superior pharmacokinetic properties and may provide patients with a more effective form of rescue therapy as well as being a reliable adjuvant or replacement for first-line oral therapy.

Cell transplantation therapies have been used to treat certain neurodegenerative diseases such as Parkinson's and Huntington's disease. However, ethical concerns over the use of fetal tissues, and the inherent complexities of standardising the procurement, processing and transplantation methods of this tissue, have prompted the search for a source of cells that have less ethical stigmatisations, are readily available and can be easily standardised. Several sources of human cells that meet these principles have been under investigation. Cells from human umbilical cord blood (HUCB) are one source that is consistent with these principles; therefore, they have become of great interest in the field of cellular repair/replacement for the treatment of CNS diseases and injury. This review will focus on the advantages of HUCB cells as a source for cellular transplantation therapies, recent studies that have examined the potential of these cells in vitro to be directed towards neural phenotypes, and in vivo studies that have investigated the functional recovery of animals in a number of models of CNS injury and disease following administration of HUCB cells.

Biohybrid implants represent a new class of medical device in which living cells, supported in a hydrogel matrix, and surrounded by a semipermiable membrane, produce and deliver therapeutic reagents to specific sites within a host. First proposed in the mid-1970s for diabetes, this treatment modality has progressed rapidly in the past four years and is now being investigated not just for endocrine disorders but also for alleviation of chronic pain, treatment of neurodegenerative disorders, and delivery of neurotrophic factors to sites within the blood brain barrier, and as a practical alternative to conventional ex vivo.

Difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (ODC; 200-800 mg/kg, s.c.), to rats has no detectable behavioral effects using a battery of tests to assess sensorimotor function. In contrast, the induction of tremor by chlordecone, a neurotoxic agent that affects neuronal ionic processes, is significantly attenuated by pretreatment with DFMO. The effects of DFMO on chlordecone-induced tremor were reversed by pretreatment with putrescine. DFMO had no effects on p,p'-DDT, a tremorigen having a mechanism of action different from chlordecone. These findings imply that polyamines may play a role in select neuronal processes.