Longitudinal Patterns of Postfracture Outpatient Physical Therapy and Occupational Therapy Use and Its Association With 3-Year Mortality Among Adults With Cerebral Palsy.

OBJECTIVE: Fragility fractures are common among adults with cerebral palsy (CP), but clinical rehabilitation use after fracture and its effect on long-term health outcomes have not been sufficiently studied. The objectives of this study were to identify patterns of the use of physical therapy, occupational therapy, or both in the 6-month postfracture period and the association with 3-year mortality in adults with CP. METHODS: This retrospective cohort study included adults who were ≥18 years old, had CP, and had sustained an incident fragility fracture between January 1, 2014, and December 31, 2016, as identified from a random 20% Medicare fee-for-service dataset. Six-month outpatient physical therapy or occupational therapy use patterns after fracture were identified using group-based trajectory modeling. Cox regression determined the association between physical therapy or occupational therapy use trajectory patterns and mortality from 6 months to 3 years after fracture, adjusting for confounders. Effect modification by key characteristics was tested, including age, sex, and the modified Whitney Comorbidity Index (mWCI), which is a CP-specific comorbidity index that better captures overall medical complexity. RESULTS: Of the 2429 participants included, the majority (73.2%) were characterized as having little to no probability of physical therapy or occupational therapy use, whereas 16.0 and 10.7% were characterized as having early initiation and later initiation, respectively. Compared to the mortality rate for the little to no physical therapy or occupational therapy group, the mortality rates were 26% lower for the early physical therapy or occupational therapy initiation group (hazard ratio [HR] = 0.74; 95% CI = 0.55-1.00) and were 20% lower for the later initiation group (HR = 0.80; 95% CI = 0.57-1.12). There was effect modification by the mWCI. The mortality rate was lower when the early initiation and later initiation groups were compared to the little to no initiation group across all mWCI values examined (median and interquartile range), but the effect was stronger (ie, lower mortality rate) for lower mWCI values for both early initiation and later initiation groups. CONCLUSION: Most adults with CP underutilize outpatient physical therapy or occupational therapy services within 6 months postfracture. Early or later initiation versus little to no physical therapy or occupational therapy use was associated with a lower HR of mortality, although the effect was stronger and statistically significant among those with less medical complexity. IMPACT: Throughout their lives, the use of rehabilitation services in individuals with CP, including physical therapy and occupational therapy, dramatically declines despite the need for continued rehabilitation across their lifespans. This study characterized longitudinal physical therapy or occupational therapy use patterns in the 6 months following a fragility fracture among adults with CP and found that nearly 3 in 4 adults with CP had little to no physical therapy or occupational therapy use during this critical window to optimize postfracture health and function. Further, those who more regularly used physical therapy or occupational therapy services, regardless of the timing of initiation (early vs later), had significantly improved survival up to 3 years after fracture, suggesting the need for greater access to and delivery of clinical rehabilitation services.

Tissue Engineered Bands of Büngner for Accelerated Motor and Sensory Axonal Outgrowth.

Following peripheral nerve injury comprising a segmental defect, the extent of axon regeneration decreases precipitously with increasing gap length. Schwann cells play a key role in driving axon re-growth by forming aligned tubular guidance structures called bands of Büngner, which readily occurs in distal nerve segments as well as within autografts - currently the most reliable clinically-available bridging strategy. However, host Schwann cells generally fail to infiltrate large-gap acellular scaffolds, resulting in markedly inferior outcomes and motivating the development of next-generation bridging strategies capable of fully exploiting the inherent pro-regenerative capability of Schwann cells. We sought to create preformed, implantable Schwann cell-laden microtissue that emulates the anisotropic structure and function of naturally-occurring bands of Büngner. Accordingly, we developed a biofabrication scheme leveraging biomaterial-induced self-assembly of dissociated rat primary Schwann cells into dense, fiber-like three-dimensional bundles of Schwann cells and extracellular matrix within hydrogel micro-columns. This engineered microtissue was found to be biomimetic of morphological and phenotypic features of endogenous bands of Büngner, and also demonstrated 8 and 2× faster rates of axonal extension in vitro from primary rat spinal motor neurons and dorsal root ganglion sensory neurons, respectively, compared to 3D matrix-only controls or planar Schwann cells. To our knowledge, this is the first report of accelerated motor axon outgrowth using aligned Schwann cell constructs. For translational considerations, this microtissue was also fabricated using human gingiva-derived Schwann cells as an easily accessible autologous cell source. These results demonstrate the first tissue engineered bands of Büngner (TE-BoBs) comprised of dense three-dimensional bundles of longitudinally aligned Schwann cells that are readily scalable as implantable grafts to accelerate axon regeneration across long segmental nerve defects.

A tissue-engineered rostral migratory stream for directed neuronal replacement.

New neurons are integrated into the circuitry of the olfactory bulb throughout the lifespan in the mammalian brain-including in humans. These new neurons are born in the subventricular zone and subsequently mature as they are guided over long distances via the rostral migratory stream through mechanisms we are only just beginning to understand. Regeneration after brain injury is very limited, and although some neuroblasts from the rostral migratory stream will leave the path and migrate toward cortical lesion sites, this neuronal replacement is generally not sustained and therefore does not provide enough new neurons to alleviate functional deficits. Using newly discovered microtissue engineering techniques, we have built the first self-contained, implantable constructs that mimic the architecture and function of the rostral migratory stream. This engineered microtissue emulates the dense cord-like bundles of astrocytic somata and processes that are the hallmark anatomical feature of the glial tube. As such, our living microtissue-engineered rostral migratory stream can serve as an in vitro test bed for unlocking the secrets of neuroblast migration and maturation, and may potentially serve as a living transplantable construct derived from a patient's own cells that can redirect their own neuroblasts into lesion sites for sustained neuronal replacement following brain injury or neurodegenerative disease. In this paper, we summarize the development of fabrication methods for this microtissue-engineered rostral migratory stream and provide proof-of-principle evidence that it promotes and directs migration of immature neurons.

Tissue engineered nigrostriatal pathway for treatment of Parkinson's disease.

The classic motor deficits of Parkinson's disease are caused by degeneration of dopaminergic neurons in the substantia nigra pars compacta, resulting in the loss of their long-distance axonal projections that modulate the striatum. Current treatments only minimize the symptoms of this disconnection as there is no approach capable of replacing the nigrostriatal pathway. We are applying microtissue engineering techniques to create living, implantable constructs that mimic the architecture and function of the nigrostriatal pathway. These constructs consist of dopaminergic neurons with long axonal tracts encased within hydrogel microcolumns. Microcolumns were seeded with dopaminergic neuronal aggregates, while lumen extracellular matrix, growth factors, and end targets were varied to optimize cytoarchitecture. We found a 10-fold increase in axonal outgrowth from aggregates versus dissociated neurons, resulting in remarkable axonal lengths of over 6 mm by 14 days and 9 mm by 28 days in vitro. Axonal extension was also dependent upon lumen extracellular matrix, but did not depend on growth factor enrichment or neuronal end target presence. Evoked dopamine release was measured via fast scan cyclic voltammetry and synapse formation with striatal neurons was observed in vitro. Constructs were microinjected to span the nigrostriatal pathway in rats, revealing survival of implanted neurons while maintaining their axonal projections within the microcolumn. Lastly, these constructs were generated with dopaminergic neurons differentiated from human embryonic stem cells. This strategy may improve Parkinson's disease treatment by simultaneously replacing lost dopaminergic neurons in the substantia nigra and reconstructing their long-projecting axonal tracts to the striatum.