Background. The skin’s uppermost layer, the stratum corneum is a very effective barrier against the penetration of compounds including pharmaceuticals and cosmetic actives. To deliver higher amounts ...of drugs into the skin layers or to deliver drugs deeper into the skin (e.g., into the dermis), several enhancement techniques have been established. These techniques include chemical penetration enhancers as well as physical techniques such as iontophoresis and microneedles. In addition, one of the newer approaches includes the use of nano-based carriers such as metallic nanoparticles and polymeric self-assembling nanospheres.
Methods. This mini-review explores this new approach of using nano-based drug carriers for skin penetration enhancement. In particular we will explore the use of gold nanoparticles as well as biocompatible tyrosine-derived polymeric nanoparticles known as Tyrospheres.
Results. The most investigated carriers in the class of metallic carriers are gold nanoparticles that can be used for both medical as well as diagnostic uses. Many investigators have reported that gold nanoparticles are able to enhance the skin transport and delivery of macromolecular and hydrophilic drugs. Meanwhile, for challenging highly lipophilic and/or unstable compounds such as adapalene and Vitamin D3 packaging them into polymeric nanocarriers such as Tyrospheres enables drug delivery to hair follicles, significantly increased aqueous solubility and resulted in elevated amounts of drug in targeted skin layers.
Conclusions. The relatively new approach of using nanotechnological approaches as a way of enhancement of drug delivery to skin shows significant promise over some other established techniques such as the addition of chemical penetration enhancers to formulations used for topical/transdermal uses.
Much of the priorities in drug delivery research are focused on targeted drug delivery for cancer therapies and a wide range of controlled drug release systems for commonly used active pharmaceutical ...ingredients (APIs). In this “thousand words article” we highlight some of the emerging health threats and future opportunities for drug delivery research.
Important emerging health threats include viral pandemics beyond COVID, antibiotic-resistant pathogens, the need for new antifungal therapies, and emerging diseases caused by increasing pollution and climate change. Fundamentally new drugs may be needed. For example, one little known research effort focuses on the development of new antibiotics based on metal-organic frameworks. Finally, new delivery approaches will be needed. This is illustrated by the development of a topical peptide delivery system as a wound dressing for burn patients, combining biotechnology (a new peptide) with polymer science (a new topical delivery system) to address a medical need (burn injury) for which there is currently no effective treatment. Another important trend is the shift in our collective understanding of impact, moving away from “counting papers” to considering the societal benefit of the research including its potential for commercialization. To remain relevant in the coming decade, we need to anticipate and embrace future challenges. This is particularly important for younger scientists.
From protein science, it is well understood that ordered folding and 3D structure mainly arise from balanced and noncovalent polar and nonpolar interactions, such as hydrogen bonding. Similarly, it ...is understood that single-chain polymer nanoparticles (SCNPs) will also compact and become more rigid with greater hydrophobicity and intrachain hydrogen bonding. Here, we couple high throughput photoinduced electron/energy transfer reversible addition–fragmentation chain-transfer (PET-RAFT) polymerization with high throughput small-angle X-ray scattering (SAXS) to characterize a large combinatorial library (>450) of several homopolymers, random heteropolymers, block copolymers, PEG-conjugated polymers, and other polymer-functionalized polymers. Coupling these two high throughput tools enables us to study the major influence(s) for compactness and flexibility in higher breadth than ever before possible. Not surprisingly, we found that many were either highly disordered in solution, in the case of a highly hydrophilic polymer, or insoluble if too hydrophobic. Remarkably, we also found a small group (9/457) of PEG-functionalized random heteropolymers and block copolymers that exhibited compactness and flexibility similar to that of bovine serum albumin (BSA) by dynamic light scattering (DLS), NMR, and SAXS. In general, we found that describing a rough association between compactness and flexibility parameters (R g/R h and Porod exponent, respectively) with log P, a quantity that describes hydrophobicity, helps to demonstrate and predict material parameters that lead to SCNPs with greater compactness, rigidity, and stability. Future implementation of this combinatorial and high throughput approach for characterizing SCNPs will allow for the creation of detailed design parameters for well-defined macromolecular chemistry.
Chronic wounds remain a large problem in the field of medicine and are often associated with risk of infection and amputation. Recently, a commercially available human cryopreserved viable amniotic ...membrane (hCVAM) has been shown to effectively promote wound closure and reduce wound-related infections. A sprevious study indicates that hCVAM can inhibit the growth of bacteria associated with chronic wounds. In the present study, we investigated the mechanism of hCVAM antimicrobial activity. Our data demonstrate that antimicrobial activities against common pathogens in chronic wounds such as P.aeruginosa, S.aureus and Methicillin-resistant S.aureus (MRSA) are mediated via the secretion of soluble factors by viable cells in hCVAM and that these factors are proteins in nature. Further, we show that genes for antimicrobial peptides (AMPs) including human beta-defensins (HBDs) are expressed by hCVAM and that expression levels positively correlate with antimicrobial activity of hCVAM. At the protein level, our data indicate that HBD2 and HBD3 are secreted by hCVAM and directly contribute to its activity against P. aeruginosa. These data provide evidence that soluble factors including AMPs are hCVAM antimicrobial agents and are consistent with a role for AMPs in mediating antimicrobial properties of the membrane.
Cell replacement therapy with human pluripotent stem cell-derived neurons has the potential to ameliorate neurodegenerative dysfunction and central nervous system injuries, but reprogrammed neurons ...are dissociated and spatially disorganized during transplantation, rendering poor cell survival, functionality and engraftment in vivo. Here, we present the design of three-dimensional (3D) microtopographic scaffolds, using tunable electrospun microfibrous polymeric substrates that promote in situ stem cell neuronal reprogramming, neural network establishment and support neuronal engraftment into the brain. Scaffold-supported, reprogrammed neuronal networks were successfully grafted into organotypic hippocampal brain slices, showing an ∼ 3.5-fold improvement in neurite outgrowth and increased action potential firing relative to injected isolated cells. Transplantation of scaffold-supported neuronal networks into mouse brain striatum improved survival ∼ 38-fold at the injection site relative to injected isolated cells, and allowed delivery of multiple neuronal subtypes. Thus, 3D microscale biomaterials represent a promising platform for the transplantation of therapeutic human neurons with broad neuro-regenerative relevance.
Abstract Nanofiber scaffolds are effective for tissue engineering since they emulate the fibrous nanostructure of native extracellular matrix (ECM). Although electrospinning has been the most common ...approach for fabricating nanofiber scaffolds, airbrushing approaches have also been advanced for making nanofibers. For airbrushing, compressed gas is used to blow polymer solution through a small nozzle which shears the polymer solution into fibers. Our goals were 1) to assess the versatility of airbrushing, 2) to compare the properties of airbrushed and electrospun nanofiber scaffolds and 3) to test the ability of airbrushed nanofibers to support stem cell differentiation. The results demonstrated that airbrushing could produce nanofibers from a wide range of polymers and onto a wide range of targets. Airbrushing was safer, 10-fold faster, 100-fold less expensive to set-up and able to deposit nanofibers onto a broader range of targets than electrospinning. Airbrushing yielded nanofibers that formed loosely packed bundles of aligned nanofibers, while electrospinning produced un-aligned, single nanofibers that were tightly packed and highly entangled. Airbrushed nanofiber mats had larger pores, higher porosity and lower modulus than electrospun mats, results that were likely caused by the differences in morphology (nanofiber packing and entanglement). Airbrushed nanofiber scaffolds fabricated from 4 different polymers were each able to support osteogenic differentiation of primary human bone marrow stromal cells (hBMSCs). Finally, the differences in airbrushed versus electrospun nanofiber morphology caused differences in hBMSC shape where cells had a smaller spread area and a smaller volume on airbrushed nanofiber scaffolds. These results highlight the advantages and disadvantages of airbrushing versus electrospinning nanofiber scaffolds and demonstrate that airbrushed nanofiber scaffolds can support stem cell differentiation.
Stem cells that adopt distinct lineages cannot be distinguished based on traditional cell shape. This study reports that higher-order variations in cell shape and cytoskeletal organization that occur ...within hours of stimulation forecast the lineage commitment fates of human mesenchymal stem cells (hMSCs). The unique approach captures numerous early (24 h), quantitative features of actin fluororeporter shapes, intensities, textures, and spatial distributions (collectively termed morphometric descriptors). The large number of descriptors are reduced into "combinations" through which distinct subpopulations of cells featuring unique combinations are identified. We demonstrate that hMSCs cultured on fibronectin-treated glass substrates under environments permissive to bone lineage induction could be readily discerned within the first 24 h from those cultured in basal- or fat-inductive conditions by such cytoskeletal feature groupings. We extend the utility of this approach to forecast osteogenic stem cell lineage fates across a series of synthetic polymeric materials of diverse physicochemical properties. Within the first 24 h following stem cell seeding, we could successfully "profile" the substrate responsiveness prospectively in terms of the degree of bone versus nonbone predisposition. The morphometric methodology also provided insights into how substrates may modulate the pace of osteogenic lineage specification. Cells on glass substrates deficient in fibronectin showed a similar divergence of lineage fates, but delayed beyond 48 h. In summary, this high-content imaging and single cell modeling approach offers a framework to elucidate and manipulate determinants of stem cell behaviors, as well as to screen stem cell lineage modulating materials and environments.
Functionalization of surfaces with poly(sodium styrenesulfonate) (poly(NaSS)) has recently been found to enhance osteointegration of implantable materials. Radical polymerization of poly(NaSS) on ...titanium (Ti)-based substrates has been used to improve their long-term performance by preventing fibrosis and consequently implant loosening. However, the influence of the sulfonate groups on the early cell behavior and the associated molecular phenomena remains to be understood. In this work, we used quartz crystal microbalance with dissipation (QCM-D) to elucidate the role of poly(NaSS) in enhancing osteoblastic cell attachment. This was measured by following the cell attachment using the MC3T3-E1 cell line, on fetal bovine serum (FBS) preadsorbed surfaces and on substrates adsorbed with a series of relevant proteins, bovine serum albumin (BSA), fibronectin (Fn), and collagen type I (Col I). Comparison of the performance of poly(NaSS) with other clinically important substrates such as Ti alloy Ti6Al4V, gold, and poly(desamino-tyrosyl-tyrosine ethyl ester carbonate) (poly(DTEc)) indicates poly(NaSS) to be a superior substrate for MC3T3-E1 cells attachment. This attachment was found to be integrin mediated in the presence of Fn and Col I. Antibodies specific to the RGD peptide and the N- and C-terminal HB-binding domains reacted more intensively with Fn adsorbed on poly(NaSS). Fn adapts a conformation favorable to RGD mediated cell attachment when adsorbed onto poly(NaSS).
Currently used methods to repair craniomaxillofacial (CMF) bone and tooth defects require a multi-staged surgical approach for bone repair followed by dental implant placement. Our previously ...published results demonstrated significant bioengineered bone formation using human dental pulp stem cell (hDPSC)-seeded tyrosine-derived polycarbonate scaffolds (E1001(1K)-bTCP). Here, we improved upon this approach using a modified TyroFill (E1001(1K)/dicalcium phosphate dihydrate (DCPD)) scaffold-supported titanium dental implant model for simultaneous bone-dental implant repair. TyroFill scaffolds containing an embedded titanium implant, with (
= 3 each time point) or without (
= 2 each time point) seeded hDPCs and Human Umbilical Vein Endothelial Cells (HUVECs), were cultured in vitro. Each implant was then implanted into a 10 mm full-thickness critical-sized defect prepared on a rabbit mandibulee. After 1 and 3 months, replicate constructs were harvested and analyzed using Micro-CT histological and IHC analyses. Our results showed significant new bone formation surrounding the titanium implants in cell-seeded TyroFill constructs. This study indicates the potential utility of hDPSC/HUVEC-seeded TyroFill scaffolds for coordinated CMF bone-dental implant repair.
Human amniotic fluid (AF) contains numerous nutrients, trophic factors and defense proteins that provide a nurturing and protective environment for fetal development. Based on reports that AF has ...antibacterial, anti-inflammatory and regenerative properties, we designed a novel method to process AF for use in clinical care.
Six randomly selected lots of processed AF (pAF) were examined to determine whether they retained their antibacterial activity against a panel of wound-associated pathogens E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and E. aerogenes (ESKAPE). To identify proteins in pAF that might be responsible for its antibacterial activity, three different lots of pAF were analyzed with quantitative cytokine arrays that consisted of 400 unique human proteins. One protein identified by microarrays, lactoferrin, and a second prominent antibacterial protein that was not identified by microarrays, lysozyme, were examined by depletion experiments to determine their contribution to the antibacterial activity of pAF.
All six lots of pAF exhibited antibacterial activity against ESKAPE microorganisms, especially against the pathogens predominately found in chronic wounds (i.e. S. aureus and P. aeruginosa). Thirty-one of the peptides on the microarray were annotated as having antibacterial activity and 26 of these were detected in pAF. Cystatin C and lactoferrin were among the most highly expressed antibacterial proteins in pAF. Cystatin C and lactoferrin were confirmed by ELISA to be present in pAF along with lysozyme. Immunoprecipitation of lactoferrin and lysozyme reduced, but did not abolish the antibacterial activities of pAF.
Our data demonstrate that pAF maintains antibacterial activity via the preservation of antibacterial proteins against a broad spectrum of wound-associated pathogens.
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