26 results found
Plotczyk M, Francesco J, Limbu S, et al., 2023, Anagen hair follicles transplanted into mature human scars remodel fibrotic tissue, Regenerative Medicine, Vol: 8, ISSN: 1746-0751
Despite the substantial impact of skin scarring on patients and the healthcare system, there is a lack of strategies to prevent scar formation, let alone methods to remodel mature scars. Here, we took a unique approach inspired by how healthy hairbearing skin undergoes physiological remodelling during the regular cycling of hair follicles. In this pilot clinical study, we tested if hair follicles transplanted into human scars can facilitate tissue regeneration and actively remodel fibrotic tissue, similar to how they remodel the healthy skin. We collected full-thickness skin biopsies and compared the morphology and transcriptional signature of fibrotic tissue before and after transplantation. We found that hair follicle tranplantation induced an increase in the epidermal thickness, interdigitation of the epidermal-dermal junction, dermal cell density, and blood vessel density. Remodelling of collagen type I fibres reduced the total collagen fraction, the proportion of thick fibres, and their alignment. Consistent with these morphological changes, we found a shift in the cytokine milieu of scars with a long-lasting inhibition of pro-fibrotic factors TGFβ1, IL13, and IL-6. Our results show that anagen hair follicles can attenuate the fibrotic phenotype, providing new insights for developing regenerative approaches to remodel mature scars.
Stejskalova A, Vankelecom H, Sourouni M, et al., 2021, In vitro modelling of the physiological and diseased female reproductive system, Acta Biomaterialia, Vol: 132, Pages: 288-312, ISSN: 1742-7061
The maladies affecting the female reproductive tract (FRT) range from infections to endometriosis to carcinomas. In vitro models of the FRT play an increasingly important role in both basic and translational research, since the anatomy and physiology of the FRT of humans and other primates differ significantly from most of the commonly used animal models, including rodents. Using organoid culture to study the FRT has overcome the longstanding hurdle of maintaining epithelial phenotype in culture. Both ECM-derived and engineered materials have proved critical for maintaining a physiological phenotype of FRT cells in vitro by providing the requisite 3D environment, ligands, and architecture. Advanced materials have also enabled the systematic study of factors contributing to the invasive metastatic processes. Meanwhile, microphysiological devices make it possible to incorporate physical signals such as flow and cyclic exposure to hormones. Going forward, advanced materials compatible with hormones and optimised to support FRT-derived cells' long-term growth, will play a key role in addressing the diverse array of FRT pathologies and lead to impactful new treatments that support the improvement of women's health.
Duran Mota JA, Quintanas Yani J, Almquist B, et al., 2021, Polyplex-loaded hydrogels for local gene delivery to human dermal fibroblasts, ACS Biomaterials Science and Engineering, Vol: 7, Pages: 4347-4361, ISSN: 2373-9878
Impaired cutaneous healing leading to chronic wounds affects between 2 and 6% of the total population in most developed countries and it places a substantial burden on healthcare budgets. Current treatments involving antibiotic dressings and mechanical debridement are often not effective, causing severe pain, emotional distress, and social isolation in patients for years or even decades, ultimately resulting in limb amputation. Alternatively, gene therapy (such as mRNA therapies) has emerged as a viable option to promote wound healing through modulation of gene expression. However, protecting the genetic cargo from degradation and efficient transfection into primary cells remain significant challenges in the push to clinical translation. Another limiting aspect of current therapies is the lack of sustained release of drugs to match the therapeutic window. Herein, we have developed an injectable, biodegradable and cytocompatible hydrogel-based wound dressing that delivers poly(β-amino ester)s (pBAEs) nanoparticles in a sustained manner over a range of therapeutic windows. We also demonstrate that pBAE nanoparticles, successfully used in previous in vivo studies, protect the mRNA load and efficiently transfect human dermal fibroblasts upon sustained release from the hydrogel wound dressing. This prototype wound dressing technology can enable the development of novel gene therapies for the treatment of chronic wounds.
Pop MA, Almquist BD, 2021, Controlled Delivery of MicroRNAs into Primary Cells Using Nanostraw Technology, Advanced NanoBiomed Research, Vol: 1, Pages: 2170063-2170063, ISSN: 2699-9307
Pop MA, Almquist BD, 2021, Controlled Delivery of MicroRNAs into Primary Cells Using Nanostraw Technology, Advanced NanoBiomed Research, Vol: 1, Pages: 2000061-2000061, ISSN: 2699-9307
Oliva N, Almquist BD, 2020, Spatiotemporal delivery of bioactive molecules for wound healing using stimuli-responsive biomaterials., Adv Drug Deliv Rev, Vol: 161-162, Pages: 22-41
Wound repair is a fascinatingly complex process, with overlapping events in both space and time needed to pave a pathway to successful healing. This additional complexity presents challenges when developing methods for the controlled delivery of therapeutics for wound repair and tissue engineering. Unlike more traditional applications, where biomaterial-based depots increase drug solubility and stability in vivo, enhance circulation times, and improve retention in the target tissue, when aiming to modulate wound healing, there is a desire to enable localised, spatiotemporal control of multiple therapeutics. Furthermore, many therapeutics of interest in the context of wound repair are sensitive biologics (e.g. growth factors), which present unique challenges when designing biomaterial-based delivery systems. Here, we review the diverse approaches taken by the biomaterials community for creating stimuli-responsive materials that are beginning to enable spatiotemporal control over the delivery of therapeutics for applications in tissue engineering and regenerative medicine.
Choi KY, Han HS, Lee ES, et al., 2019, Hyaluronic acid-based activatable nanomaterials for stimuli-responsive imaging and therapeutics: beyond CD44-mediated drug delivery, Advanced Materials, Vol: 31, ISSN: 0935-9648
There is a rapidly increasing interest in developing stimuli-responsive nanomaterials for treating a variety of diseases. By enabling the activation of function locally at the sites of interest, it is possible to increase therapeutic efficacy significantly while simultaneously reducing adverse side effects. While there are many sophisticated nanomaterials available, they are many times highly complex and not easily transferrable to industrial scales and clinical settings. However, hyaluronic acid-based nanomaterials offer a compelling strategy for reducing the complexity of nanomaterials while retaining several desirable benefits such as active targeting and stimuli-responsive degradation. In this report, we cover the basic properties of hyaluronic acid, its binding partners, and natural routes for degradation by hyaluronidases—hyaluronic acid-degrading enzymes—and oxidative stresses. We then cover recent advances in designing hyaluronic acid-based, actively targeted, hyaluronidase- or reactive oxygen species-responsive nanomaterials for both diagnostic imaging and therapeutic delivery that go beyond merely the classical targeting of CD44.
Stejskalova A, Oliva N, England FJ, et al., 2019, Biologically Inspired, Cell-Selective Release of Aptamer-Trapped Growth Factors by Traction Forces, ADVANCED MATERIALS, Vol: 31, ISSN: 0935-9648
- Author Web Link
- Open Access Link
- Citations: 41
Sun J, Almquist BD, 2018, Interfacial contact is required for metal-assisted plasma etching of silicon, Advanced Materials Interfaces, Vol: 5, Pages: 1-8, ISSN: 2196-7350
For decades, fabrication of semiconductor devices has utilized well‐established etching techniques to create complex nanostructures in silicon. The most common dry process is reactive ion etching which fabricates nanostructures through the selective removal of unmasked silicon. Generalized enhancements of etching have been reported with mask‐enhanced etching with Al, Cr, Cu, and Ag masks, but there is a lack of reports exploring the ability of metallic films to catalytically enhance the local etching of silicon in plasmas. Here, metal‐assisted plasma etching (MAPE) is performed using patterned nanometers‐thick gold films to catalyze the etching of silicon in an SF6/O2 mixed plasma, selectively increasing the rate of etching by over 1000%. The catalytic enhancement of etching requires direct Si‐metal interfacial contact, similar to metal‐assisted chemical etching (MACE), but is different in terms of the etching mechanism. The mechanism of MAPE is explored by characterizing the degree of enhancement as a function of Au catalyst configuration and relative oxygen feed concentration, along with the catalytic activities of other common MACE metals including Ag, Pt, and Cu.
Kiani MT, Higgins CA, Almquist BD, 2018, The Hair Follicle: An Underutilized Source of Cells and Materials for Regenerative Medicine, ACS BIOMATERIALS SCIENCE & ENGINEERING, Vol: 4, Pages: 1193-1207, ISSN: 2373-9878
- Author Web Link
- Open Access Link
- Citations: 15
Stejskalova A, Almquist BD, 2017, Using biomaterials to rewire the process of wound repair, BIOMATERIALS SCIENCE, Vol: 5, Pages: 1421-1434, ISSN: 2047-4830
- Author Web Link
- Open Access Link
- Citations: 35
Pop MA, Sun JB, Almquist BD, 2017, Biomaterial-Based Systems for Pharmacologic Treatment of Wound Repair, Bioengineering in Wound Healing: A Systems Approach, Editors: Yarmush, Golberg, Publisher: World Scientific, ISBN: 978-981-3144-57-6
Pop MA, Almquist BD, 2017, Biomaterials: a potential pathway to healing chronic wounds?, Experimental Dermatology, Vol: 26, Pages: 760-763, ISSN: 1600-0625
Chronic dermal wounds are a devastating problem that disproportionally affect individuals with conditions such as diabetes, paralysis, or simply old age. These wounds are extremely challenging to treat due to a heterogeneous combination of causative factors, creating a substantial burden on healthcare systems worldwide. Despite their large impact, there is currently a startling lack of options for effectively treating the underlying biological changes that occur within the wounds. Biomaterials possess an enticing ability to provide new comprehensive approaches to healing these devastating wounds; advanced wound dressings are now being developed that enable the ability to coordinate temporal delivery of multiple therapeutics, protect sensitive biologics from degradation, and provide supportive matrices that encourage the growth of tissue. This positions biomaterials as a potential ‘conductor’ of wound repair, allowing them to simultaneously address numerous barriers to healing, and in turn providing a promising pathway to innovative new technologies for driving successful healing.
Castleberry SA, Golberg A, Sharkh MA, et al., 2016, Nanolayered siRNA delivery platforms for local silencing of CTGF reduce cutaneous scar contraction in third-degree burns., Biomaterials, Vol: 95, Pages: 22-34
Wound healing is an incredibly complex biological process that often results in thickened collagen-enriched healed tissue called scar. Cutaneous scars lack many functional structures of the skin such as hair follicles, sweat glands, and papillae. The absence of these structures contributes to a number of the long-term morbidities of wound healing, including loss of function for tissues, increased risk of re-injury, and aesthetic complications. Scar formation is a pervasive factor in our daily lives; however, in the case of serious traumatic injury, scars can create long-lasting complications due to contraction and poor tissue remodeling. Within this report we target the expression of connective tissue growth factor (CTGF), a key mediator of TGFβ pro-fibrotic response in cutaneous wound healing, with controlled local delivery of RNA interference. Through this work we describe both a thorough in vitro analysis of nanolayer coated sutures for the controlled delivery of siRNA and its application to improve scar outcomes in a third-degree burn induced scar model in rats. We demonstrate that the knockdown of CTGF significantly altered the local expression of αSMA, TIMP1, and Col1a1, which are known to play roles in scar formation. The knockdown of CTGF within the healing burn wounds resulted in improved tissue remodeling, reduced scar contraction, and the regeneration of papillary structures within the healing tissue. This work adds support to a number of previous reports that indicate CTGF as a potential therapeutic target for fibrosis. Additionally, we believe that the controlled local delivery of siRNA from ultrathin polymer coatings described within this work is a promising approach in RNA interference that could be applied in developing improved cancer therapies, regenerative medicine, and fundamental scientific research.
Stejskalova A, Kiani MT, Almquist BD, 2016, Programmable biomaterials for dynamic and responsive drug delivery, EXPERIMENTAL BIOLOGY AND MEDICINE, Vol: 241, Pages: 1127-1137, ISSN: 1535-3702
- Author Web Link
- Open Access Link
- Citations: 6
Castleberry SA, Almquist BD, Li W, et al., 2016, Self-Assembled Wound Dressings Silence MMP-9 and Improve Diabetic Wound Healing In Vivo., Adv Mater, Vol: 28, Pages: 1809-1817
The direct local delivery of short interfering RNA (siRNA) into target tissues presents a real solution to several complex medical conditions that today lack efficacious therapies. The development of an ultrathin polymer coating is described to sustain the delivery of siRNA for up to 2 weeks in vitro and in vivo. This technology successfully reduces the expression of MMP-9 within the wounds of diabetic mice, significantly accelerating the wound healing process and improving the quality of tissue formed.
Almquist BD, Castleberry SA, Sun JB, et al., 2015, Combination Growth Factor Therapy via Electrostatically Assembled Wound Dressings Improves Diabetic Ulcer Healing In Vivo., Adv Healthc Mater, Vol: 4, Pages: 2090-2099
Chronic skin ulcerations are a common complication of diabetes mellitus, affecting up to one in four diabetic individuals. Despite the prevalence of these wounds, current pharmacologic options for treating them remain limited. Growth factor-based therapies have displayed a mixed ability to drive successful healing, which may be due to nonoptimal delivery strategies. Here, a method for coating commercially available nylon dressings using the layer-by-layer process is described to enable both sustained release and independent control over the release kinetics of vascular endothelial growth factor 165 and platelet-derived growth factor BB. It is shown that the use of strategically spaced diffusion barriers formed spontaneously by disulfide bonds enables independent control over the release rates of incorporated growth factors, and that in vivo these dressings improve several aspects of wound healing in db/db mice.
Almquist BD, Melosh NA, Verma P, 2014, Devices and Methods for Long-term Intracellular Access, 8,808,516 B2
Nanoscale probes for forming stable, non-destructive seals with cell membranes. The probes, systems including these probes, and methods of fabricating and using the probes described herein may be used to sense from, stimulate, modify, or otherwise effect individual cells or groups of cells. In particular, described herein are nanoscale cellular probes that may be used to span the lipid membrane of a cell to provide stable and long lasting access to the internal cellular structures. Thus, the probes described herein may be used as part of a system, method or device that would benefit from stable, non-destructive access across a cell membrane. In some variations the nanoscale probe devices or systems described herein may be used as part of a drug screening procedure.
Almquist BD, Melosh NA, 2011, Molecular structure influences the stability of membrane penetrating biointerfaces., Nano Lett, Vol: 11, Pages: 2066-2070
Nanoscale patterning of hydrophobic bands on otherwise hydrophilic surfaces allows integration of inorganic structures through biological membranes, reminiscent of transmembrane proteins. Here we show that a set of innate molecular properties of the self-assembling hydrophobic band determine the resulting interface stability. Surprisingly, hydrophobicity is found to be a secondary factor with monolayer crystallinity the major determinate of interface strength. These results begin to establish guidelines for seamless bioinorganic integration of nanoscale probes with lipid membranes.
Almquist BD, Verma P, Cai W, et al., 2011, Nanoscale patterning controls inorganic-membrane interface structure., Nanoscale, Vol: 3, Pages: 391-400
The ability to non-destructively integrate inorganic structures into or through biological membranes is essential to realizing full bio-inorganic integration, including arrayed on-chip patch-clamps, drug delivery, and biosensors. Here we explore the role of nanoscale patterning on the strength of biomembrane-inorganic interfaces. AFM measurements show that inorganic probes functionalized with hydrophobic bands with thicknesses complimentary to the hydrophobic lipid bilayer core exhibit strong attachment in the bilayer. As hydrophobic band thickness increases to 2-3 times the bilayer core the interfacial strength decreases, comparable to homogeneously hydrophobic probes. Analytical calculations and molecular dynamics simulations predict a transition between a 'fused' interface and a 'T-junction' that matches the experimental results, showing lipid disorder and defect formation for thicker bands. These results show that matching biological length scales leads to more intimate bio-inorganic junctions, enabling rational design of non-destructive membrane interfaces.
Wong IY, Almquist BD, Melosh NA, 2010, Dynamic actuation using nano-bio interfaces, Materials Today, Vol: 13, Pages: 14-22, ISSN: 1369-7021
The nanoscale dimensions, sensitive electronic control, and flexible architecture of new generations of nanomaterials and nanofabrication techniques hold immense promise not only for electronic devices, but also biological interfaces. As the size scales of these materials approach biological species, interfaces with characteristics designed to emulate their nanoscale biological counterparts are becoming possible. These new systems have higher biocompatibility, functionality, and lower cell toxicity than their microscale predecessors. While stellar examples have been demonstrated for biomolecular detection and imaging, exciting new possibilities for long-term integration and dynamic stimulation are now emerging, including protein activation, membrane integration and intracellular delivery. These tailored interfaces may lead to improved regenerative medicine, gene therapy and neural prosthetics.
Almquist BD, Melosh NA, 2010, Fusion of biomimetic stealth probes into lipid bilayer cores., Proc Natl Acad Sci U S A, Vol: 107, Pages: 5815-5820
Many biomaterials are designed to regulate the interactions between artificial and natural surfaces. However, when materials are inserted through the cell membrane itself the interface formed between the interior edge of the membrane and the material surface is not well understood and poorly controlled. Here we demonstrate that by replicating the nanometer-scale hydrophilic-hydrophobic-hydrophilic architecture of transmembrane proteins, artificial "stealth" probes spontaneously insert and anchor within the lipid bilayer core, forming a high-strength interface. These nanometer-scale hydrophobic bands are readily fabricated on metallic probes by functionalizing the exposed sidewall of an ultrathin evaporated Au metal layer rather than by lithography. Penetration and adhesion forces for butanethiol and dodecanethiol functionalized probes were directly measured using atomic force microscopy (AFM) on thick stacks of lipid bilayers to eliminate substrate effects. The penetration dynamics were starkly different for hydrophobic versus hydrophilic probes. Both 5- and 10 nm thick hydrophobically functionalized probes naturally resided within the lipid core, while hydrophilic probes remained in the aqueous region. Surprisingly, the barrier to probe penetration with short butanethiol chains (E(o,5 nm) = 21.8k(b)T, E(o,10 nm) = 15.3k(b)T) was dramatically higher than longer dodecanethiol chains (E(o,5 nm) = 14.0k(b)T, E(o,10 nm) = 10.9k(b)T), indicating that molecular mobility and orientation also play a role in addition to hydrophobicity in determining interface stability. These results highlight a new strategy for designing artificial cell interfaces that can nondestructively penetrate the lipid bilayer.
Mager MD, Almquist B, Melosh NA, 2008, Formation and Characterization of Fluid Lipid Bilayers on Alumina, Langmuir, Vol: 24, Pages: 12734-12737, ISSN: 0743-7463
Fluid lipid bilayers were deposited on alumina substrates with the use of bubble collapse deposition (BCD). Previous studies using vesicle rupture have required the use of charged lipids or surface functionalization to induce bilayer formation on alumina, but these modifications are not necessary with BCD. Photobleaching experiments reveal that the diffusion coefficient of POPC on alumina is 0.6 μm2/s, which is much lower than the 1.4-2.0 μm2/s reported on silica. Systematically accounting for roughness, immobile regions and membrane viscosity shows that pinning sites account for about half of this drop in diffusivity. The remainder of the difference is attributed to a more tightly bound water state on the alumina surface, which induces a larger drag on the bilayer.
Duran-Mota JA, Quintanas Yani J, Almquist B, et al., Polyplex-Loaded Hydrogels for Local Gene Delivery to Human Dermal Fibroblasts, Publisher: American Chemical Society (ACS)
<jats:p>Impaired cutaneous healing, leading to chronic wounds, affects between 2 and 6% of the total population in most developed countries and it places a substantial burden on healthcare budgets. Current treatments involving antibiotic dressings and mechanical debridement are often not effective, causing severe pain, emotional distress and social isolation in patients for years or even decades, ultimately resulting in limb amputation. Alternatively, gene therapy (such as mRNA therapies) emerges as a viable option to promote wound healing through modulation of gene expression. However, protecting the genetic cargo from degradation and efficient transfection into primary cells remain significant challenges in the push to clinical translation. Another limiting aspect of current therapies is the lack of sustained release of drugs to match the therapeutic window. Herein, we have developed an injectable, biodegradable and biocompatible hydrogel-based wound dressing that delivers pBAE nanoparticles in a sustained manner over a range of therapeutic windows. We also demonstrate that pBAE nanoparticles, successfully used in previous <jats:italic>in vivo</jats:italic> studies, protect the mRNA load and efficiently transfect human dermal fibroblasts upon sustained release from the hydrogel wound dressing. This prototype wound dressing technology can enable the development of novel gene therapies for the treatment of chronic wounds.</jats:p>
Sun J, Almquist B, Metal-Assisted Plasma Etching of Silicon: A Liquid-Free Alternative to MACE
<jats:p>For decades, fabrication of semiconductor devices has utilized well-established etching techniques to create complex nanostructures in silicon. Of these, two of the most common are reactive ion etching in the gaseous phase and metal-assisted chemical etching (MACE) in the liquid phase. Though these two methods are highly established and characterized, there is a surprising scarcity of reports exploring the ability of metallic films to catalytically enhance the etching of silicon in dry plasmas via a MACE-like mechanism. Here, we discuss a <jats:underline>m</jats:underline>etal-<jats:underline>a</jats:underline>ssisted <jats:underline>p</jats:underline>lasma <jats:underline>e</jats:underline>tch (MAPE) performed using patterned gold films to catalyze the etching of silicon in an SF<jats:sub>6</jats:sub>/O<jats:sub>2</jats:sub> mixed plasma, selectively increasing the rate of etching by over 1000%. The degree of enhancement as a function of Au catalyst configuration and relative oxygen feed concentration is characterized, along with the catalytic activities of other common MACE metals including Ag, Pt, and Cu. Finally, methods of controlling the etch process are briefly explored to demonstrate the potential for use as a liquid-free fabrication strategy.</jats:p>
Duran-Mota JA, Quintanas Yani J, Almquist B, et al., Polyplex-Loaded Hydrogels for Local Gene Delivery to Human Dermal Fibroblasts
<jats:p>Impaired cutaneous healing, leading to chronic wounds,affects between 2 and 6% of the total population in most developed countriesand it places a substantial burden on healthcare budgets. Current treatmentsinvolving antibiotic dressings and mechanical debridement are often noteffective, causing severe pain, emotional distress and social isolation inpatients for years or even decades, ultimately resulting in limb amputation.Alternatively, gene therapy (such as mRNA therapies) emerges as a viable optionto promote wound healing through modulation of gene expression. However, protectingthe genetic cargo from degradation and efficient transfection into primarycells remain significant challenges in the push to clinical translation.Another limiting aspect of current therapies is the lack of sustained releaseof drugs to match the therapeutic window. Herein, we have developed aninjectable, biodegradable and biocompatible hydrogel-based wound dressing thatdelivers pBAE nanoparticles in a sustained manner over a range of therapeuticwindows. We also demonstrate that pBAE nanoparticles, successfully used inprevious <i>in vivo</i> studies, protect the mRNA load and efficientlytransfect human dermal fibroblasts upon sustained release from the hydrogelwound dressing. This prototype wound dressing technology can enable thedevelopment of novel gene therapies for the treatment of chronic wounds.</jats:p>
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