Spinal cord injury results in significant loss of motor, sensory, and autonomic functions. Although a wide range of therapeutic agents have been shown to attenuate secondary injury or promote ...regeneration/repair in animal models of spinal cord injury, clinical translation of these strategies has been limited, in part due to difficulty in safely and effectively achieving therapeutic concentrations in the injured spinal cord tissue. Hydrogel-based drug delivery systems offer unique opportunities to locally deliver drugs to the injured spinal cord with sufficient dose and duration, while avoiding deleterious side effects associated with systemic drug administration. Such local drug delivery systems can be readily fabricated from biocompatible and biodegradable materials. In this review, hydrogel-based strategies for local drug delivery to the injured spinal cord are extensively reviewed, and recommendations are made for implementation.
Minocycline hydrochloride（MH）, a semi-synthetic tetracycline derivative, is a clinically available antibiotic and anti-inflammatory drug that also exhibits potent neuroprotective activities. It has ...been shown to target multiple secondary injury mechanisms in spinal cord injury, via its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. The secondary injury mechanisms that MH can potentially target include inflammation, free radicals and oxidative stress, glutamate excitotoxicity, calcium influx, mitochondrial dysfunction, ischemia, hemorrhage, and edema. This review discusses the potential mechanisms of the multifaceted actions of MH. Its anti-inflammatory and neuroprotective effects are partially achieved through conserved mechanisms such as modulation of p38 mitogen-activated protein kinase（MAPK） and phosphoinositide 3-kinase（PI3K）/Akt signaling pathways as well as inhibition of matrix metalloproteinases（MMPs）. Additionally, MH can directly inhibit calcium influx through the N-methyl-D-aspartate（NMDA） receptors, mitochondrial calcium uptake, poly（ADP-ribose） polymerase-1（PARP-1） enzymatic activity, and iron toxicity. It can also directly scavenge free radicals. Because it can target many secondary injury mechanisms, MH treatment holds great promise for reducing tissue damage and promoting functional recovery following spinal cord injury.
Abundant lipid-laden macrophages are found at the injury site after spinal cord injury (SCI). These cells have been suggested to be pro-inflammatory and neurotoxic. AdipoRon, an adiponectin receptor ...agonist, has been shown to promote myelin lipid efflux from mouse macrophage foam cells. While it is an attractive therapeutic strategy, systemic administration of AdipoRon is likely to exert off-target effects. In addition, the pathophysiology after SCI in mice is different from that in humans, whereas rat and human SCI share similar functional and histological outcomes. In this study, we evaluated the effects of AdipoRon on rat macrophage foam cells and developed a drug delivery system capable of providing sustained local release of AdipoRon to the injured spinal cord.
Rat macrophages were treated with myelin debris to generate an
model of SCI foam cells, and the effects of AdipoRon treatment on myelin uptake and efflux were studied. AdipoRon was then loaded into and released from microparticles made from dextran sulfate and fibrinogen for sustained release.
AdipoRon treatment not only significantly promotes efflux of metabolized myelin lipids, but also inhibits uptake of myelin debris. Myelin debris alone does not appear to be inflammatory, but myelin debris treatment potentiates inflammation when administered along with pro-inflammatory lipopolysaccharide (LPS) and interferon-
. AdipoRon significantly attenuated myelin lipid-induced potentiation of inflammation. Bioactive AdipoRon can be released in therapeutic doses from microparticles.
These data suggest that AdipoRon is a promising therapeutic capable of reducing lipid accumulation via targeting both myelin lipid uptake and efflux, which potentially addresses chronic inflammation following SCI. Furthermore, we developed microparticle-based drug delivery systems for local delivery of AdipoRon to avoid deleterious side effects. This is the first study to release AdipoRon from drug delivery systems designed to reduce lipid accumulation and inflammation in reactive macrophages after SCI.
The coronavirus disease 2019 (COVID‐19) pandemic has revealed major shortcomings in our ability to mitigate transmission of infectious viral disease and provide treatment to patients, resulting in a ...public health crisis. Within months of the first reported case in China, the virus has spread worldwide at an unprecedented rate. COVID‐19 illustrates that the biomaterials community was engaged in significant research efforts against bacteria and fungi with relatively little effort devoted to viruses. Accordingly, biomaterials scientists and engineers will have to participate in multidisciplinary antiviral research over the coming years. Although tissue engineering and regenerative medicine have historically dominated the field of biomaterials, current research holds promise for providing transformative solutions to viral outbreaks. To facilitate collaboration, it is imperative to establish a mutual language and adequate understanding between clinicians, industry partners, and research scientists. In this article, clinical perspectives are shared to clearly define emerging healthcare needs that can be met by biomaterials solutions. Strategies and opportunities for novel biomaterials intervention spanning diagnostics, treatment strategies, vaccines, and virus‐deactivating surface coatings are discussed. Ultimately this review serves as a call for the biomaterials community to become a leading contributor to the prevention and management of the current and future viral outbreaks.
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•Immunosuppressive treatments generally reduce nerve regeneration after injury.•Macrophages exhibit diverse phenotypes to guide successful nerve regeneration.•Immunomodulatory ...therapies offer promise for treating peripheral nerve injuries.
Peripheral nerve injuries result in disrupted cellular communication between the central nervous system and somatic distal end targets. The peripheral nervous system is capable of independent and extensive regeneration; however, meaningful target muscle reinnervation and functional recovery remain limited and may result in chronic neuropathic pain and diminished quality of life. Macrophages, the primary innate immune cells of the body, are critical contributors to regeneration of the injured peripheral nervous system. However, in some clinical scenarios, macrophages may fail to provide adequate support with optimal timing, duration, and location. Here, we review the history of immunosuppressive and immunomodulatory strategies to treat nerve injuries. Thereafter, we enumerate the ways in which macrophages contribute to successful nerve regeneration. We argue that implementing macrophage-based immunomodulatory therapies is a promising treatment strategy for nerve injuries across a wide range of clinical presentations.
Abstract Many mechanisms contribute to the secondary injury cascades following traumatic spinal cord injury (SCI). However, most current treatment strategies only target one or a few elements in the ...injury cascades, and have been largely unsuccessful in clinical trials. Minocycline hydrochloride (MH) is a clinically available antibiotic and anti-inflammatory drug that has been shown to target a broad range of secondary injury mechanisms via its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. However, MH is only neuroprotective at high concentrations. The inability to translate the high doses of MH used in experimental animals to tolerable doses in human patients limits its clinical efficacy. In addition, the duration of MH treatment is limited because long-term systemic administration of high doses of MH has been shown to cause liver toxicity and even death. We have developed a drug delivery system in the form of hydrogel loaded with polysaccharide-MH complexes self-assembled by metal ions for controlled release of MH. This drug delivery system can be injected into the intrathecal space for local delivery of MH with sufficient dose and duration, without causing any additional tissue damage. We show that local delivery of MH at a dose that is lower than the standard human dose (3 mg/kg) was more effective in reducing secondary injury and promoting locomotor functional recovery than systemic injection of MH with the highest dose and duration reported in experimental animal SCI (90–135 mg/kg).
Degradable polymers are often desirable for the fabrication of medical implants, but thermal processing of these polymers is a challenge. We describe here how these problems can be addressed by ...discussing the extrusion of fibers and injection molding of bone pins from a hydrolytically degradable tyrosine‐derived polycarbonate. Our initial attempts produced fibers and pins with bubbles, voids, and discoloration and resulted in the formation of large polymer plugs that seized screws and blocked extruder dies. The material and process parameters that contribute to these issues were investigated by studying the physical and chemical changes that occur during processing. Differential scanning calorimetry and thermogravimetric analysis combined with IR analysis showed that residual moisture and solvents in conjunction with heat cause degradation and crosslinking as indicated by gel permeation chromatography. Rheology and melt flow index measurements were useful in characterizing the extent of dependence of polymer viscosity on temperature and molecular weight. With these insights, we could process our polymer into fibers and rods by controlling residual moisture, time, and temperature and by adjusting processing parameters in real time. The systematic approach described here is applicable to other degradable polymers that are difficult to process.
Challenges in thermal processing of degradable polymers can be met by understanding the mechanisms of degradation‐induced changes in the polymer. Detailed characterization of the degradation products will lead to a selection of processing parameters for successful extrusion, thermoforming, and injection molding of the desired products.
Traumatic spinal cord injury (SCI) causes apoptosis of myelin-forming oligodendrocytes (OLs) and demyelination of surviving axons, resulting in conduction failure. Remyelination of surviving denuded ...axons provides a promising therapeutic target for spinal cord repair. While cell transplantation has demonstrated efficacy in promoting remyelination and functional recovery, the lack of ideal cell sources presents a major obstacle to clinical application. The adult spinal cord contains oligodendrocyte precursor cells and multipotent neural stem/progenitor cells that have the capacity to differentiate into mature, myelinating OLs. However, endogenous oligodendrogenesis and remyelination processes are limited by the upregulation of remyelination-inhibitory molecules in the post-injury microenvironment. Multiple growth factors/molecules have been shown to promote OL differentiation and myelination.
In this study we screened these therapeutics and found that 3, 3', 5-triiodothyronine (T3) is the most effective in promoting oligodendrogenesis and OL maturation in vitro. However, systemic administration of T3 to achieve therapeutic doses in the injured spinal cord is likely to induce hyperthyroidism, resulting in serious side effects.
In this study we developed a novel hydrogel-based drug delivery system for local delivery of T3 to the injury site without eliciting systemic toxicity.
Using a clinically relevant cervical contusion injury model, we demonstrate that local delivery of T3 at doses comparable to safe human doses promoted new mature OL formation and myelination after SCI.
Accurate survival stratification in early-stage non-small cell lung cancer (NSCLC) could inform the use of adjuvant therapy. We developed a clinically implementable mortality risk score incorporating ...distinct tumor microenvironmental gene expression signatures and clinical variables.
Gene expression profiles from 1106 nonsquamous NSCLCs were used for generation and internal validation of a nine-gene molecular prognostic index (MPI). A quantitative polymerase chain reaction (qPCR) assay was developed and validated on an independent cohort of formalin-fixed paraffin-embedded (FFPE) tissues (n = 98). A prognostic score using clinical variables was generated using Surveillance, Epidemiology, and End Results data and combined with the MPI. All statistical tests for survival were two-sided.
The MPI stratified stage I patients into prognostic categories in three microarray and one FFPE qPCR validation cohorts (HR = 2.99, 95% CI = 1.55 to 5.76, P < .001 in stage IA patients of the largest microarray validation cohort; HR = 3.95, 95% CI = 1.24 to 12.64, P = .01 in stage IA of the qPCR cohort). Prognostic genes were expressed in distinct tumor cell subpopulations, and genes implicated in proliferation and stem cells portended poor outcomes, while genes involved in normal lung differentiation and immune infiltration were associated with superior survival. Integrating the MPI with clinical variables conferred greatest prognostic power (HR = 3.43, 95% CI = 2.18 to 5.39, P < .001 in stage I patients of the largest microarray cohort; HR = 3.99, 95% CI = 1.67 to 9.56, P < .001 in stage I patients of the qPCR cohort). Finally, the MPI was prognostic irrespective of somatic alterations in EGFR, KRAS, TP53, and ALK.
The MPI incorporates genes expressed in the tumor and its microenvironment and can be implemented clinically using qPCR assays on FFPE tissues. A composite model integrating the MPI with clinical variables provides the most accurate risk stratification.
We designed and developed a novel library of tyrosol‐derived poly(ester‐arylate)s that exhibit tunable chemical, thermal, mechanical, and degradative properties. To build the library, the diphenols ...4‐hydroxyphenethyl 2‐(4‐hydroxyphenyl)acetate (HTy) and 4‐hydroxyphenethyl 3‐(4‐hydroxyphenyl)propanoate (DTy) are synthesized and subsequently polymerized with various diacids. Characterization of library members is performed in order to assess the impact of chemical structure on polymer properties. Specifically, the relative influence of diphenol pseudosymmetry versus asymmetry, diacid carbon chain length, and diacid bond rigidity on resulting properties is investigated. Diphenol choice greatly impacts resulting polymer thermal properties and processability. HTy‐containing polymers generally have lower melting temperatures compared to their DTy‐derived counterparts and are easier to quench in the amorphous phase. As a result, processing results in greater tunability for HTy‐derived polymers. One specific example was pHTy3, which increased its tensile modulus from 1 GPa to 3 GPa upon drawing. Diacid lengths and bond rigidity also significantly influence thermal, mechanical, and degradative properties. In all, members of this library can be synthesized efficiently, with high molecular weight and exhibit a wide range of properties, motivating future commercial translation.
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