Windebank, Anthony J.

To satisfy different mechanical requirements in hard and soft tissue replacements, a series of biodegradable and crosslinkable copolymers of poly(propylene fumarate)‐co‐polycaprolactone (PPF‐co‐PCL) are synthesized and employed to fabricate 2D disks and 3D scaffolds via photocrosslinking. Thermal properties such as the glass transition temperature (Tg) and melting temperature (Tm) of the PPF‐co‐PCL networks can be controlled efficiently by varying the PCL composition (φPCL). As a result, their mechanical properties vary significantly from hard and stiff materials to soft and flexible ones with increasing φPCL, making them attractive candidate materials for bone and peripheral nerve regeneration, respectively. Several PPF‐co‐PCL formulations are selected to perform in vitro cell studies using mouse pre‐osteoblastic MC3T3‐E1, rat Schwann cell precursor line (SPL201), and pheochromocytoma (PC12) cells, and in vivo animal testing in the rat femur bone defect model and in the rat sciatic nerve transection model. The formation of new bone in the porous bone scaffolds with a low φPCL and guided axon growth through the nerve conduits with a higher φPCL suggest that crosslinked PPF‐co‐PCLs have appropriate compatibility and functionality. Furthermore, the role of surface stiffness in modulating cellular behavior and functions is verified on the crosslinked PPF‐co‐PCL surfaces without any pretreatments.

BackgroundThere are no effective treatments that slow the progression of neurodegenerative diseases. A major challenge of treatment in neurodegenerative diseases is appropriate delivery of pharmaceuticals into the cerebrospinal fluid (CSF) of affected individuals. Mesenchymal stromal cells (MSCs—either naïve or modified) are a promising therapy in neurodegenerative diseases and may be delivered directly into the CSF where they can reside for months. In this preclinical study, we evaluated the safety of intrathecal autologous MSCs in a rabbit model.Study Design and MethodsAutologous adipose‐derived MSCs (or artificial CSF) were delivered intrathecally, either with single or with repeated injections into the foramen magnum of healthy rabbits and monitored for 4 and 12 weeks, respectively.ResultsRabbits tolerated injections well and no definitive MSC‐related side effects were observed apart from three rabbits that had delayed death secondary to traumatic foramen magnum puncture. Functional assessments and body weights were equivalent between groups. Gross pathology and histology did not reveal any abnormalities or tumor growth. Complete blood count data were normal and there were no differences in CSF interleukin‐6 levels in all groups tested.ConclusionOur data suggest that intrathecal delivery of autologous MSCs is safe in a rabbit model. Data from this study have supported two successful investigational new drug applications to the Food and Drug Administration, resulting in the initiation of two clinical trials using autologous MSCs in amyotrophic lateral sclerosis and multiple system atrophy.

Biomedical scientists can exploit initiatives from U.S. federal regulatory and funding agencies aimed at accelerating clinical translation.

ObjectiveMutations in Charcot–Marie–Tooth disease (CMT) genes are the cause of rare familial forms of polyneuropathy. Whether allelic variability in CMT genes is also associated with common forms of polyneuropathy—considered “acquired” in medical parlance—is unknown. Chemotherapy‐induced peripheral neuropathy (CIPN) occurs commonly in cancer patients and is individually unpredictable. We used CIPN as a clinical model to investigate the association of non‐CMT polyneuropathy with CMT genes.MethodsA total of 269 neurologically asymptomatic cancer patients were enrolled in the clinical trial Alliance N08C1 to receive the neurotoxic drug paclitaxel, while undergoing prospective assessments for polyneuropathy. Forty‐nine CMT genes were analyzed by targeted massively parallel sequencing of genomic DNA from patient blood.ResultsA total of 119 (of 269) patients were identified from the 2 ends of the polyneuropathy phenotype distribution: patients that were most and least susceptible to paclitaxel polyneuropathy. The CMT gene PRX was found to be deleteriously mutated in patients who were susceptible to CIPN but not in controls (p = 8 × 10−3). Genetic variation in another CMT gene, ARHGEF10, was highly significantly associated with CIPN (p = 5 × 10−4). Three nonsynonymous recurrent single nucleotide variants contributed to the ARHGEF10 signal: rs9657362, rs2294039, and rs17683288. Of these, rs9657362 had the strongest effect (odds ratio = 4.8, p = 4 × 10−4).InterpretationThe results reveal an association of CMT gene allelic variability with susceptibility to CIPN. The findings raise the possibility that other acquired polyneuropathies may also be codetermined by genetic etiological factors, of which some may be related to genes already known to cause the phenotypically related Mendelian disorders of CMT. Ann Neurol 2014;76:727–737

ABSTRACTIntroduction: Isometric muscle force measurement is a sensitive marker for motor function recovery in rat nerve repair models. Current methods of eliciting maximal isometric force with nerve stimulation cannot provide longitudinal data.Methods: We developed a novel method for measuring isometric muscle force with a device designed to allow minimally invasive nerve stimulation and measurement of plantar flexion force. This indirectly elicited muscle force was compared with muscle force elicited by direct muscle stimulation in 3 surgical models.Results: The force measured after sciatic nerve transection and repair followed a parabolic trend. There was a postinjury decrease in force that continued until postoperative day 42, after which the force increased with time, indicating muscle reinnervation.Conclusions: This approach can track longitudinal changes in force in the most common animal model for studies of clinically relevant problems in the peripheral nerve field.Muscle Nerve50: 812–821, 2014

AbstractTranslational stories range from straightforward to complex. In this commentary, the story of the rapid and successful translation of rituximab therapy for the treatment of non‐Hodgkin's lymphoma (NHL) is examined. Development of this monoclonal antibody therapy began in the late 1980s. In 1994, rituximab received its first approval for the treatment of NHL by the United States Food and Drug Administration (FDA). Rituximab has since been approved for additional indications and has transformed medical practice. However, the social and political implications of these rapid successes are only beginning to become clear. In this commentary, key events in the rapid translation of rituximab from the bench to bedside are highlighted and placed into this historical framework. To accomplish this, the story of rituximab is divided into the following six topics, which we believe to be widely applicable to case studies of translation: (1) underlying disease, (2) key basic science, (3) key clinical studies in translation, (4) FDA approval process, (5) changes to medical practice, and (6) the social and political influences on translation.