Biology subjects

von Recum, H. A.

Publications and source records attributed to von Recum, H. A..

6 recordsLinked to original sources

bioRxiv2020

Engineering Selective Molecular Tethers to Enhance Suboptimal Drug Properties

Small-molecule drugs are utilized in a wide variety of clinical applications, however, many of these drugs suffer from one or more suboptimal property that can hinder its delivery or cellular action in vivo, or even shelf an otherwise biologically tolerable drug. While high-throughput screening provides a method to discover drugs with altered chemical properties, directly engineering small-molecule bioconjugates provides an opportunity to specifically modulate drug properties rather than sifting through large drug libraries with seemingly random drug properties. Herein, we propose that selectively "tethering" a drug molecule to an additional group with favorable properties will improve the drug conjugates overall properties, such as solubility. Specifically, we outlined the site-specific chemical conjugation of rapamycin (RAP) to an additional "high-affinity" group to increase the overall affinity the drug has for cyclodextrin-based polymers (pCD). By doing so, we found that RAPs affinity for pCD and RAPs window of delivery from pCD microparticles was tripled without sacrificing RAPs cellular action. This synthesis method was applied to the concept of "affinity" for pCD, but other prosthetic groups can be used in a similar manner to modify other drug properties. This study displays potential for increasing drug delivery windows of small-molecule drugs in pCD systems for chronic drug therapies and introduces the idea of altering drug properties to tune polymer-drug interactions.

bioengineering↗

bioRxiv2020

Cyclodextrin polymer coatings resist protein fouling, mammalian cell adhesion, and bacterial attachment

Undesired attachment of proteins, cells/bacteria, and organisms on material surfaces is problematic in industrial and health care settings. In this study, polymer coatings are synthesized from subunits of cyclodextrin, an additive/excipient found in food/pharmaceutical formulations. These unique polymers, which have been applied mainly towards sustained drug delivery applications, are evaluated in this study for their ability to mitigate non-specific protein adsorption, mammalian cell (NIH/3T3) adhesion, and bacterial cell (Staphylococcus aureus, Escherichia coli) attachment. Effects of cyclodextrin polymer composition, particularly incorporation of nonpolar crosslinks, on material properties and passive anti-biofouling performance are investigated. Results suggest that lightly-crosslinked cyclodextrin polymers possess excellent passive resistance to protein, cell, and bacterial attachment, likely due to the hydrophilic and electrically neutral surface properties of these coatings. At the same time, anti-biofouling performance decreased with increasing crosslink ratios, possibly a reflection of decreased polymer mobility, increased rigidity, and increased hydrophobic character. Cyclodextrin-based materials may be broadly useful as coatings in industrial or medical applications where biofouling-resistant and/or drug-delivering surfaces are required.

bioengineering↗

bioRxiv2019

Using nonthermal plasma treatment to improve quality and durability of hydrophilic coatings on hydrophobic polymer surfaces

Low surface energy substrates, which include many polymers in medicine/industry, present challenges toward achieving uniform, adherent, durable coatings, thus limiting intended coating function. Examples include hydrophobic polymers such as polypropylene, polyethylene, polytetrafluoroethylene, and polydimethylsiloxane. These inert materials are used in various biomedical implants due to favorable bulk properties despite perhaps unfavorable surface properties. The capability to coat such materials holds great value as the surface heavily influences biological response and implant function in vivo. Likewise, paint/ink coatings are often necessary on these same plastics, as their final appearance can be critical for automotive, packaging, and consumer products. Substrate exposure to nonthermal plasma was explored here as a means to improve quality of coatings, specifically cyclodextrin-based polyurethanes previously explored for biomedical applications such as controlled drug delivery and anti-biofouling, upon otherwise incompatible polypropylene substrates. Plasma treatment was found to increase wettability and oxygen content on substrate surfaces. These plasma-induced surface alterations were associated with enhanced coating uniformity, and improved coating/substrate adherence - determined to derive partly from interfacial covalent bond formation. Findings demonstrate the utility of plasma-based surface activation as a strategy to improve coating quality on polymeric substrates, and reveal insights regarding mechanisms by which plasma improves polymer coating adherence.

bioengineering↗

bioRxiv2019

Nonthermal plasma treatment of polymers modulates biological fouling but can cause material embrittlement

Plasma-based treatment is a prevalent strategy to alter biological response and enhance biomaterial coating quality at the surfaces of biomedical devices and implants, especially polymeric materials. Plasma, an ionized gas, is often thought to have negligible effects on the bulk properties of prosthetic substrates given that it alters the surface chemistry on only the outermost few nanometers of material. However, no studies to date have systematically explored the effects of plasma exposure on both the surface and bulk properties of a biomaterial. This work examines the time-dependent effects of a nonthermal plasma on the surface and bulk properties of polymeric implants, specifically polypropylene surgical meshes and sutures. Findings suggest that plasma exposure improved resistance to fibrinogen adsorption and Escherichia coli attachment, and promoted mammalian fibroblast attachment, although increased duration of exposure resulted in a state of diminishing returns. At the same time, it was observed that plasma exposure can be detrimental to the material properties of individual filaments (i.e. sutures), as well as the structural characteristics of knitted meshes, with longer exposures resulting in further embrittlement and larger changes in anisotropic qualities. Though there are few guidelines regarding appropriate mechanical properties of surgical textiles, the results from this investigation imply that there are ultimate exposure limits for plasma-based treatments of polymeric implant materials when structural properties must be preserved, and that the effects of a plasma on a given biomaterial should be examined carefully before translation to a clinical scenario.

bioengineering↗

bioRxiv2019

Combination antibiotic delivery in PMMA provides sustained broad-spectrum antimicrobial activity and allows for post-implantation refilling

Antibiotics are commonly added to poly(methyl methacrylate) (PMMA) by surgeons to locally treat infections such as in bone cement for joint replacement surgeries, but also as implantable antimicrobial "beads". However, this strategy is of limited value in high risk patients where infections can be recurrent or chronic and otherwise hard to treat. Also when only one drug is incorporated and applied toward poly-microbial infections (multiple bacterial species), there is a high risk that bacteria can develop antibiotic resistance. To combat these limitations, we developed a combination-antibiotic PMMA composite system comprised of rifampicin-filled {beta}-cyclodextrin ({beta}-CD) microparticles added into PMMA filled with a second drug. Different formulations were evaluated through Zone-of-Inhibition, drug activity, antibiotic release and re-filling, as well as mechanical studies. Our combination-antibiotic PMMA composite system achieved up to an eight-fold increase in duration of antimicrobial activity in comparison to clinically used antibiotic-filled PMMA. Inclusion of CD microparticles also allowed for refilling of additional antibiotics after simulated implantation, resulting in additional windows of therapeutic efficacy. Mechanical testing showed that our tested formulations did have a small, but significant decrease in mechanical properties when compared to unmodified controls. While further studies are needed to determine whether the tested formulations are still suitable for load-bearing applications (e.g. bone cement), our composites are certainly amenable for a variety of non-load bearing applications (e.g. antimicrobial "beads" and temporary spacer in two-stage arthroscopic revisions).

bioengineering↗

bioRxiv2019

Affinity-based polymers provide long-term immunotherapeutic drug delivery across particle size ranges optimal for macrophage targeting

Long term drug delivery to specific arms of the immune system can be technically challenging to provide limited off-target toxicity as well as prolonged delivery and specific cellular targeting given the limits of current drug delivery systems. In this work, we demonstrate the robustness of a cyclodextrin (CD) polymer platform that can extend immunomodulatory drug delivery via affinity interactions to promote long-term, sustained release at multiple size scales. The parameter space of synthesis variables (pre-incubation and stirring speed) and post-synthesis grinding effects on resulting particle diameter were characterized. We demonstrate that polymerized CD forms exhibit size-independent release profiles of the small molecule drug lenalidomide (LND) and can provide similar drug delivery profiles as macro-scale CD polymer disks. CD polymer microparticles and nanoparticles demonstrated no significant cytotoxicity as compared to the base CD macromonomer when co-incubated with fibroblasts. Uptake of ground CD nanoparticles was significantly higher following incubation with RAW 264.7 macrophages in culture over originally synthesized, larger CD microparticles. Thus, the affinity/structure properties afforded by polymerized CD allow particle size to be modified to affect cellular uptake profiles independently of drug release rate for applications in cell-targeted drug delivery.

bioengineering↗