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1.
Nat Commun ; 10(1): 4830, 2019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645570

RESUMO

Central nervous system (CNS) injuries persist for years, and currently there are no therapeutics that can address the complex injury cascade that develops over this time-scale. 17ß-estradiol (E2) has broad tropism within the CNS, targeting and inducing beneficial phenotypic changes in myriad cells following injury. To address the unmet need for vastly prolonged E2 release, we report first-generation poly(pro-E2) biomaterial scaffolds that release E2 at nanomolar concentrations over the course of 1-10 years via slow hydrolysis in vitro. As a result of their finely tuned properties, these scaffolds demonstrate the ability to promote and guide neurite extension ex vivo and protect neurons from oxidative stress in vitro. The design and testing of these materials reported herein demonstrate the first step towards next-generation implantable biomaterials with prolonged release and excellent regenerative potential.


Assuntos
Astrócitos/efeitos dos fármacos , Materiais Biocompatíveis , Estradiol/farmacologia , Estrogênios/farmacologia , Gânglios Espinais/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Fármacos do Sistema Nervoso Central/administração & dosagem , Fármacos do Sistema Nervoso Central/química , Fármacos do Sistema Nervoso Central/farmacologia , Implantes de Medicamento/química , Estradiol/administração & dosagem , Estradiol/química , Estrogênios/administração & dosagem , Estrogênios/química , Técnicas In Vitro , Macrófagos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Polímeros/química , Cultura Primária de Células , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Ratos , Medula Espinal/citologia
2.
Brain Res Bull ; 150: 216-230, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31173859

RESUMO

Gene therapy is a promising form of treatment for those suffering from neurological disorders or central nervous system (CNS) injury, however, obstacles remain that limit its translational potential. The CNS is protected by the blood brain barrier, and this barrier blocks genes from traversing into the CNS if administered outside of the CNS. Viral and non-viral gene delivery vehicles, commonly referred to as vectors, are modified to enhance delivery efficiency to target locations in the CNS. Still, there are few gene therapy approaches approved by the FDA for CNS disease or injury treatment. The lack of viable clinical approaches is due, in part, to the unpredictable nature of many vector systems. In particular, safety concerns exist with the use of viral vectors for CNS gene delivery. To seek some alternatives to viral vectors, development of new non-viral, biomaterial vectors is occurring at a rapid rate. This review discusses the challenges of delivering various forms of genetic material to the CNS, the use and limitations of current viral vector delivery systems, and the use of non-viral, biomaterial vectors for CNS applications.

3.
ACS Appl Bio Mater ; 2(4): 1498-1508, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-31061988

RESUMO

Macrophages are immune cells involved in wound healing and tissue regeneration; however, the sustained presence of proinflammatory macrophages in wound sites impairs healing. In this study, we shifted peritoneal macrophage polarization away from a proinflammatory (M1) phenotype through exposure to stabilized interleukin-4 (IL-4) in poly(lactic-co-glycolic acid) films in combination with topographical guidance from electrospun poly-L-lactic acid fibers. To our knowledge, this was the first study to stabilize IL-4 with bovine serum albumin (BSA) within a biomaterial. When IL-4 was coloaded with BSA for stabilization, we saw increased IL-4 bioactivity compared to no added stabilization, trehalose stabilization, or murine serum albumin stabilization. We observed increased elongation of peritoneal macrophages, increased RNA expression of anti-inflammatory marker arginase-1, increased ratio of interleukin-10/interleukin- 12 p40 RNA, and decreased protein expression of proinflammatory markers (interleukin-12 p40 and RANTES) compared to controls. Taken together, these results suggest the macrophages were less proinflammatory and were a more pro-resolving phenotype. When stabilized with BSA, IL-4-loaded films effectively shift macrophage polarization state and are thus promising scaffolds to reduce inflammation within in vivo injury models.

4.
PLoS One ; 14(2): e0211731, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30716106

RESUMO

Three aligned, electrospun fiber scaffolds with unique surface features were created from poly-L-lactic acid (PLLA). Fibers without surface nanotopography (smooth fibers), fibers with surface divots (shallow pits), and fibers with surface pits (deeper pits) were fabricated, and fiber alignment, diameter, and density were characterized using scanning electron microscopy (SEM). Whole dorsal root ganglia (DRG) were isolated from rats and placed onto uncoated fibers or fibers coated with laminin. On uncoated fibers, neurite outgrowth was restricted by fibers displaying divoted or pitted nanotopography when compared to neurite outgrowth on smooth fibers. However, neurites extending from whole DRG cultured on laminin-coated fibers were not restricted by divoted or pitted surface nanotopography. Thus, neurites extending on laminin-coated fibers were able to extend long neurites even in the presence of surface divots or pits. To further explore this result, individual neurons isolated from dissociated DRG were seeded onto laminin-coated smooth, pitted, or divoted fibers. Interestingly, neurons on pitted or divoted fibers exhibited a 1.5-fold increase in total neurite length, and a 2.3 or 2.7-fold increase in neurite branching compared to neurons on smooth fibers, respectively. Based on these findings, we conclude that fiber roughness in the form of pits or divots can promote extension and branching of long neurites along aligned electrospun fibers in the presence of an extracellular matrix protein coating. Thus, aligned, electrospun fibers can be crafted to not only direct the extension of axons but to induce unique branching morphologies.


Assuntos
Neuritos/fisiologia , Crescimento Neuronal/fisiologia , Neurônios/fisiologia , Animais , Proteínas da Matriz Extracelular/metabolismo , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiologia , Microscopia Eletrônica de Varredura/métodos , Nanotecnologia/métodos , Regeneração Nervosa/fisiologia , Neuritos/metabolismo , Neurônios/metabolismo , Poliésteres/química , Ratos , Ratos Sprague-Dawley , Engenharia Tecidual/métodos , Tecidos Suporte
5.
Biomed Mater ; 13(5): 054101, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29762127

RESUMO

Aligned, electrospun fiber scaffolds provide topographical guidance for regenerating neurons and glia after central nervous system injury. To date, no study has explored how fiber surface nanotopography affects astrocyte response to fibrous scaffolds. Astrocytes play important roles in the glial scar, the blood brain barrier, and in maintaining homeostasis in the central nervous system. In this study, electrospun poly L-lactic acid fibers were engineered with smooth, pitted, or divoted surface nanotopography. Cortical or spinal cord primary rat astrocytes were cultured on the surfaces for either 1 or 3 d to examine the astrocyte response over time. The results showed that cortical astrocytes were significantly shorter and broader on the pitted and divoted fibers compared to those on smooth fibers. However, spinal cord astrocyte morphology was not significantly altered by the surface features. These findings indicate that astrocytes from unique anatomical locations respond differently to the presence of nanotopography. Western blot results show that the differences in morphology were not associated with significant changes in glial fibrillary acidicprotein (GFAP) or vinculin in either astrocyte population, suggesting that surface pits and divots do not induce a reactive phenotype in either cortical or spinal cord astrocytes. Finally, astrocytes were co-cultured with dorsal root ganglia to determine how the surfaces affected astrocyte-mediated neurite outgrowth. Astrocytes cultured on the fibers for shorter periods of time (1 d) generally supported longer neurite outgrowth. Pitted and divoted fibers restricted spinal cord astrocyte-mediated neurite outgrowth, while smooth fibers increased 3 d spinal cord astrocyte-mediated neurite outgrowth. In total, fiber surface nanotopography can influence astrocyte elongation and influence the capability of astrocytes to direct neurites. Therefore, fiber surface characteristics should be carefully controlled to optimize astrocyte-mediated axonal regeneration.


Assuntos
Astrócitos/citologia , Nanoestruturas , Neuritos/fisiologia , Neuroglia/patologia , Animais , Sistema Nervoso Central/lesões , Sistema Nervoso Central/patologia , Técnicas de Cocultura , Gânglios Espinais/citologia , Proteína Glial Fibrilar Ácida/metabolismo , Microscopia Eletrônica de Varredura , Regeneração Nervosa , Crescimento Neuronal , Neurônios/citologia , Ratos , Ratos Sprague-Dawley , Medula Espinal/patologia , Tecidos Suporte , Vinculina/metabolismo
6.
Electrospinning ; 2(1): 15-28, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31032427

RESUMO

Electrospinning is a robust material fabrication method allowing for fine control of mechanical, chemical, and functional properties in scaffold manufacturing. Electrospun fiber scaffolds have gained prominence for their potential in a variety of applications such as tissue engineering and textile manufacturing, yet none have assessed the impact of solvent retention in fibers on the scaffold's mechanical properties. In this study, we hypothesized that retained electrospinning solvent acts as a plasticizer, and gradual solvent evaporation, by storing fibers in ambient air, will cause significant increases in electrospun fiber scaffold brittleness and stiffness, and a significant decrease in scaffold toughness. Thermogravimetric analysis indicated solvent retention in PGA, PLCL, and PET fibers, and not in PU and PCL fibers. Differential scanning calorimetry revealed that polymers that were electrospun below their glass transition temperature (T g ) retained solvent and polymers electrospun above T g did not. Young's moduli increased and yield strain decreased for solventretaining PGA, PLCL, and PET fiber scaffolds as solvent evaporated from the scaffolds over a period of 14 days. Toughness and failure strain decreased for PGA and PET scaffolds as solvent evaporated. No significant differences were observed in the mechanical properties of PU and PCL scaffolds that did not retain solvent. These observations highlight the need to consider solvent retention following electrospinning and its potential effects on scaffold mechanical properties.

7.
Polymer (Guildf) ; 123: 121-127, 2017 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-29200507

RESUMO

A major challenge in developing drug-releasing electrospun nanofibers is obtaining long-term drug release over many weeks with no burst release of drug. Here, we present new methods capable of prolonging the diffusive release of small molecule drugs from electrospun poly-L-lactic acid (PLLA) nanofibers. The methods focus on removal of retained electrospinning solvent through fiber heating, maintaining fibers in a laboratory setting, or a combination of these methods. These post-fabrication methods altered the release characteristics of a model small molecule drug, 6-aminonicotinamide (6AN), from PLLA fibers. Specifically, untreated fibers released 6AN over 9 days, and fibers that underwent a combined treatment of maintenance in a laboratory setting and heating released 6AN over 44 days. The unique and simple method presented here prolongs diffusive release of a small molecule drug from electrospun fibers and has potential to assist in lengthening small molecule drug release from a variety of polymeric nanomaterials.

8.
J Biomater Sci Polym Ed ; 28(13): 1303-1323, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28420296

RESUMO

Currently, it is unknown how the mechanical properties of electrospun fibers, and the presentation of surface nanotopography influence macrophage gene expression and protein production. By further elucidating how specific fiber properties (mechanical properties or surface properties) alter macrophage behavior, it may be possible to create electrospun fiber scaffolds capable of initiating unique cellular and tissue responses. In this study, we determined the elastic modulus and rigidity of fibers with varying topographies created by finely controlling humidity and including a non-solvent during electrospinning. In total,five fiber scaffold types were produced. Analysis of fiber physical properties demonstrated no change in fiber diameter amongst the five different fiber groups. However, the four different fibrous scaffolds with nanopits or divots each possessed different numbers of pits with different nanoscale dimensions. Unpolarized bone marrow derived murine macrophages (M0), macrophages polarized towards a pro-inflammatory phenotype (M1), or macrophages polarized towards anti-inflammatory phenotype (M2b) were placed onto each of the scaffolds and cytokine RNA expression and protein production were analyzed. Specific nanotopographies did not appreciably alter cytokine production from undifferentiated macrophages (M0) or anti-inflammatory macrophages (M2b), but a specific fiber (with many small pits) did increase IL-12 transcript and IL-12 protein production compared to fibers with small divots. When analyzing the mechanical properties between fibers with divots or with many small pits,divoted fibers possessed similar elastic moduli but different stiffness values. In total,we present techniques capable of creating unique electrospun fibers. These unique fibers have varying fiber mechanical characteristics and modestly modulate macrophage cytokine expression.


Assuntos
Citocinas/biossíntese , Eletricidade , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Nanotecnologia/métodos , Tecidos Suporte/química , Animais , Células da Medula Óssea/citologia , Macrófagos/citologia , Fenômenos Mecânicos , Camundongos , Células RAW 264.7 , Propriedades de Superfície
9.
Cells Tissues Organs ; 202(1-2): 116-135, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27701153

RESUMO

There is currently no cure for individuals with spinal cord injury (SCI). While many promising approaches are being tested in clinical trials, the complexity of SCI limits several of these approaches from aiding complete functional recovery. Several different categories of biomaterials are investigated for their ability to guide axonal regeneration, to deliver proteins or small molecules locally, or to improve the viability of transplanted stem cells. The purpose of this study is to provide a brief overview of SCI, present the different categories of biomaterial scaffolds that direct and guide axonal regeneration, and then focus specifically on electrospun fiber guidance scaffolds. Much like other polymer guidance approaches, electrospun fibers can retain and deliver therapeutic drugs. The experimental section presents new data showing the incorporation of two therapeutic drugs into electrospun poly-L-lactic acid fibers. Two different concentrations of either riluzole or neurotrophin-3 were loaded into the electrospun fibers to examine the effect of drug concentration on the physical characteristics of the fibers (fiber alignment and fiber diameter). Overall, the drugs were successfully incorporated into the fibers and the release was related to the loading concentration. The fiber diameter decreased with the inclusion of the drug, and the decreased diameter was correlated with a decrease in fiber alignment. Subsequently, the study includes considerations for successful incorporation of a therapeutic drug without changing the physical properties of the fibers.


Assuntos
Sistemas de Liberação de Medicamentos , Poliésteres/química , Traumatismos da Medula Espinal/tratamento farmacológico , Engenharia Tecidual/métodos , Animais , Humanos , Microscopia Eletrônica de Varredura , Neurotrofina 3/uso terapêutico , Riluzol/uso terapêutico
10.
Conf Proc IEEE Eng Med Biol Soc ; 2015: 3691-4, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26737094

RESUMO

Increasing the numbers of black, latino and native youth in STEM careers is both an important way to reduce poverty in low income communities, and a contribution to the diversity of thought and experience that drives STEM research. But underrepresented youth are often alienated from STEM. Two new forms of social capital have been identified that can be combined to create a learning environment in which students and researchers can meet and explore an area of shared interest. Experimental capital refers to the intrinsic motivation that students can develop when they learn inquiry techniques for exploring topics that they feel ownership over. Credentialing capital denotes a shared interest and ability between all parties engaged in the experimental endeavor. These two forms of social capital form an adaptable framework for researchers to use to create effective outreach programs. In this case study sports biomechanics was utilized as the area of shared interest and understanding the slam dunk was used as experimental capital.


Assuntos
Relações Comunidade-Instituição , Educação/métodos , Ciência , Adolescente , Credenciamento , Feminino , Humanos , Masculino , Motivação , Pobreza , Esportes , Estudantes , Populações Vulneráveis
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