Oxidation Reduction Potential (ORP) is Predictive of Complications Following Pediatric Cardiac Surgery.

Oxidation reduction potential (ORP) or Redox is the ratio of activity between oxidizers and reducers. Oxidative stress (OS) can cause cellular injury and death, and is important in the regulation of immune response to injury or disease. In the present study, we investigated changes in the redox system as a function of cardiopulmonary bypass (CPB) in pediatric patients. 664 plasma samples were collected from 162 pediatric patients having cardiac surgery of various CPB times. Lower ORP values at 12 h post-CPB were associated with poor survival rate (mean ± SD 167 ± 20 vs. 138 ± 19, p = 0.005) and higher rate of thrombotic complications (153 ± 21 vs. 168 ± 20, p < 0.008). Similarly, patients who developed infections had lower ORP values at 6 h (149 ± 19 vs. 160 ± 22, p = 0.02) and 12 h (156 ± 17 vs. 168 ± 21, p = 0.004) post-CPB. Patients that developed any post-operative complication also had lower 6 h (149 ± 17 vs. 161 ± 23, p = 0.002) and 12 h (157 ± 18 vs. 170 ± 21, p = 0.0007) post-CPB ORP values. Free hemoglobin and IL-6, IL-10, and CRP were not associated with ORP levels. However, higher haptoglobin levels preoperatively were protective against decreases in ORP. Decreased ORP is a marker for poor outcome and predictive of post-operative thrombosis, infection, and other complications in critically ill pediatric cardiac surgery patients. These results suggest that redox imbalance and OS may contribute to the risk of complications and poor outcome in pediatric CBP patients. Haptoglobin may be a marker for increased resilience to OS in this population.

Comparison of fetal mesencephalic grafts, AAV-delivered GDNF, and both combined in an MPTP-induced nonhuman primate Parkinson's model.

We combined viral vector delivery of human glial-derived neurotrophic factor (GDNF) with the grafting of dopamine (DA) precursor cells from fetal ventral mesencephalon (VM) to determine whether these strategies would improve the anti-Parkinson's effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, an animal model for Parkinson's disease (PD). Both strategies have been reported as individually beneficial in animal models of PD, leading to clinical studies. GDNF delivery has also been reported to augment VM tissue implants, but no combined studies have been done in monkeys. Monkeys were treated with MPTP and placed into four balanced treatment groups receiving only recombinant adeno-associated virus serotype 5 (rAAV5)/hu-GDNF, only fetal DA precursor cells, both together, or a buffered saline solution (control). The combination of fetal precursors with rAAV5/hu-GDNF showed significantly higher striatal DA concentrations compared with the other treatments, but did not lead to greater functional improvement in this study. For the first time under identical conditions in primates, we show that all three treatments lead to improvement compared with control animals.

30 years of American Society for Neural Therapy and Repair (ASNTR): A personal perspective at the intersection of science, politics, and culture.

The American Society for Neural Therapy and Repair (ASNTR) started 30 years ago in 1993 as the American Society for Neural Transplantation (ASNT), with an emphasis on neural transplantation. Through the years, the Society has been shaped as much by our expanding knowledge of neurodegenerative disorders and how to treat them as it has by politics and culture. What once felt like a leash on neuroscience research, has turned into an advantage as neural transplantation evolved into Neural Therapy and Repair. As a Co-Founder this brief commentary provides a personalized account of our research during the Society's years.

Persistent dyskinesias in patients with fetal tissue transplantation for Parkinson disease.

Cell transplants are being developed for patients with Parkinson disease (PD) who have insufficient benefit with standard medical treatment. We describe the clinical features of five patients who developed persistent dyskinesias after fetal dopaminergic tissue transplantation. All had levodopa-induced dyskinesias preoperatively. We implanted fetal mesencephalic dopaminergic tissue into the putamina bilaterally in 34 patients with advanced PD. They were not immunosuppressed. Five of 34 patients (15%) developed troublesome choreic or dystonic dyskinesias that persisted despite lowering or discontinuing medications. Attempts to treat the involuntary movements with amantadine, clozapine, anticholinergics, dopamine depletors and other medicines had limited success. Metyrosine eliminated dyskinesias but led to the parkinsonian "off" state. Increasing the dose of levodopa worsened the dyskinesias. Three patients required placement of pallidal stimulators, bilaterally in two and unilaterally in one patient who had only contralateral dyskinesias. The two with the bilateral stimulators had improvement in dyskinesias. The patient with the unilateral pallidal stimulator had a substantial reduction of the dyskinesias, but attempts to treat residual "off" symptoms with levodopa were limited by worsening dyskinesias. Although the number of patients developing these persistent dyskinesias was small, these five patients had dramatic improvement after transplant. As a group, they had milder Parkinson signs at baseline and improved to the point of having minimal parkinsonism, with reduction or elimination of levodopa therapy prior to developing persistent dyskinesias. These involuntary movements establish the principle that fetal dopaminergic tissue transplants can mimic the effects of levodopa, not only in reducing bradykinesia, but also in provoking dyskinesias.

Impact of lactic acid on cell proliferation and free radical-induced cell death in monolayer cultures of neural precursor cells.

Biomaterials prepared from polyesters of lactic acid and glycolic acid, or a mixture of the two, degrade in the presence of water into the naturally occurring metabolites, lactic acid and glycolic acid. While the lactic acid degradation product that is released from biomaterials is well tolerated by the body, lactic acid can influence the metabolic function of cells; it can serve as an energy substrate for cells, and has been shown to have antioxidant properties. Neural precursor cells, a cell population of considerable interest as a source of cells for neural tissue regeneration strategies, generate a high amount of reactive oxygen species, and when associated with a degradable biomaterial, may be impacted by released lactic acid. In this work, the effect of lactic acid on a neural cell population containing proliferative neural precursor cells was examined in monolayer culture. Lactic acid was found to scavenge exogenously added free radicals produced in the presence of either hydrogen peroxide or a photoinitiator (I2959) commonly utilized in the preparation of photopolymerizable biomaterials. In addition to its effect on exogenously added free radicals, lactic acid reduced intracellular redox state, increased the proliferation of the cell population, and modified the cell composition. The findings of this study provide insight into the role that lactic acid plays naturally on developing neural cells and are also of interest to biomaterials scientists that are focused on the development of degradable lactic-acid-based polymers for cell culture devices. The effect of lactic acid on other cell populations may differ and should be characterized to best understand how cells function in degradable cell culture devices.

Poor acute outcome in congestive heart failure is associated with increases in the plasma static oxidation-reduction potentials (sORP) in men but not in women.

OBJECTIVES: In congestive heart failure (CHF), men are younger, more likely to have reduced ejection fraction (HF-rEF), and to be diabetic compared to women. Despite this, sex differences in oxidative stress have yet to be explored in CHF. METHODS: Data from 67 males and 63 females hospitalized for CHF were collected. Static oxidation-reduction potential (sORP), a relative indicator of oxidative stress, and capacity ORP (icORP), a relative indicator of antioxidant capacity, were measured from plasma samples. We examined whether sex modified the relationship between ORP and hospital discharge disposition (poor outcome: death, hospice), along with other demographics, medications, and diagnostic parameters. RESULTS: Males with poor outcomes had higher sORP and icORP values than females (P < 0.05). For those with a good outcome, there were no differences between the sexes (P > 0.05). Males were younger and more likely to have HF-rEF and diabetes. Controlling for these variables did not account for the sex differences in ORP measures. Regardless of sex, higher creatinine was related to higher sORP and icORP, while lower magnesium and potassium were related to higher sORP and icORP, respectively. DISCUSSION: Increases in sORP during CHF are partially affected by sex and acute outcomes, but are also related to variables without sexual biases.

Redox Changes in Amateur Race Car Drivers Before and After Racing.

Despite the unique opportunity race car driving provides to study exercise in extreme conditions, the sport of racing is under-represented. A better understanding of how racing changes physiological measures combined with driver demographics may help reduce driver risks and expand the field of driver science. This study charted the changes in heart rate, body temperature, blood pressure, static oxidation reduction potential (sORP), and antioxidant capacity in drivers before and after racing (n=23). The interaction between racing and driver characteristics on physiological variables were evaluated. Heart rate, body temperature, and sORP were elevated after racing (P<0.05). Age, cockpit temperature, experience, and speed did not correlate with physiological or oxidative measures (P>0.05). Elevated post-race sORP values were associated with higher pre-race systolic blood pressure and lower antioxidant capacity (P<0.05). We conclude that racing alters the redox response in drivers and that drivers' pre-race systolic blood pressure and antioxidant capacity can further alter it. A better understanding of the physical and oxidative changes which result from racing may help minimize the unique risks.

Oxidation-reduction potential of semen: what is its role in the treatment of male infertility?

The diagnosis of male infertility relies largely on conventional semen analysis, and its interpretation has a profound influence on subsequent management of patients. Despite poor correlation between conventional semen parameters and male fertility potential, inclusion of advanced semen quality tests to routine male infertility workup algorithms has not been widely accepted. Oxidative stress is one of the major mediators in various etiologies of male infertility; it has deleterious effects on spermatozoa, including DNA damage. Alleviation of oxidative stress constitutes a potential treatment strategy for male infertility. Measurement of seminal oxidative stress is of crucial role in the identification and monitoring of patients who may benefit from treatments. Various tests including reactive oxygen species (ROS) assay, total antioxidant capacity (TAC) assay or malondialdehyde (MDA) assay used by different laboratories have their own drawbacks. Oxidation-reduction potential (ORP) is a measure of overall balance between oxidants and antioxidants, providing a comprehensive measure of oxidative stress. The MiOXSYS™ System is a novel technology based on a galvanostatic measure of electrons; it presents static ORP (sORP) measures with static referring to the passive or current state of activity between oxidants and antioxidants. Preliminary studies have correlated sORP to poor semen qualities. It is potentially useful in prognostication of assisted reproductive techniques outcomes, screening of antioxidants either in vivo or during IVF cycles, identification of infertile men who may benefit from treatment of oxidative stress, and monitoring of treatment success. The simplified laboratory test requiring a small amount of semen would facilitate clinical application and research in the field. In this paper, we discuss the measurement of ORP by the MiOXSYS System as a real-time assessment of seminal oxidative stress, and argue that it is a potential valuable clinical test that should be incorporated into the male infertility workup and become an important guide to the treatment of oxidative stress-induced male infertility.

Oxidation-Reduction Potential as a Biomarker for Severity and Acute Outcome in Traumatic Brain Injury.

There are few reliable markers for assessing traumatic brain injury (TBI). Elevated levels of oxidative stress have been observed in TBI patients. We hypothesized that oxidation-reduction potential (ORP) could be a potent biomarker in TBI. Two types of ORP were measured in patient plasma samples: the static state of oxidative stress (sORP) and capacity for induced oxidative stress (icORP). Differences in ORP values as a function of time after injury, severity, and hospital discharge were compared using ANOVAs with significance at p ≤ 0.05. Logit regression analyses were used to predict acute outcome comparing ORP, Injury Severity Score (ISS), Abbreviated Injury Scale (AIS), and Glasgow Coma Scale (GCS). Antioxidant capacity (icORP) on day 4 was prognostic for acute outcomes (p < 0.05). An odds ratio of 4.08 was associated with poor acute outcome when icORP > 7.25 µC. IcORP was a better predictor than ISS, AIS, or GCS scores. sORP increased in those with the highest ISS values (p < 0.05). Based on these findings ORP is useful biomarker for severity and acute outcome in TBI patients. Changes in ORP values on day 4 after injury were the most prognostic, suggesting that patients' response to brain injury over time is a factor that determines outcome.

Neural stem cells implanted into MPTP-treated monkeys increase the size of endogenous tyrosine hydroxylase-positive cells found in the striatum: a return to control measures.

Neural stem cells (NSC) have been shown to migrate towards damaged areas, produce trophic factors, and replace lost cells in ways that might be therapeutic for Parkinson's disease (PD). However, there is very little information on the effects of NSC on endogenous cell populations. In the current study, effects of implanted human NSC (hNSC) on endogenous tyrosine hydroxylase-positive cells (TH+ cells) after treatment with 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) were explored in nonhuman primates. After MPTP damage and in PD, the primate brain is characterized by decreased numbers of dopamine neurons in the substantia nigra (SN) and an increase in neurons expressing TH in the caudate nucleus. To determine how implanted NSC might affect these cell populations, 11 St. Kitts African green monkeys were treated with the selective dopaminergic neurotoxin, MPTP. Human NSC were implanted into the left and right caudate nucleus and the right SN of eight of the MPTP-treated monkeys. At either 4 or 7 months after NSC implants, the brains were removed and the size and number of TH+ cells in the target areas were assessed. The results were compared to data obtained from normal untreated control monkeys and to the three unimplanted MPTP-treated monkeys. The majority of hNSC were found bilaterally along the nigrostriatal pathway and in the substantia nigra, while relatively few were found in the caudate. In the presence of NSC, the number and size of caudate TH+ cells returned to non-MPTP-treated control levels. MPTP-induced and hNSC-induced changes in the putamen were less apparent. We conclude that after MPTP treatment in the primate, hNSC prevent the MPTP-induced upregulation of TH+ cells in the caudate and putamen, indicating that hNSC may be beneficial to maintaining a normal striatal environment.

Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial.

CONTEXT: This study was part of a large double-blind sham surgery-controlled trial designed to determine the effectiveness of transplantation of human embryonic dopamine neurons into the brains of persons with advanced Parkinson's disease. This portion of the study investigated the quality of life (QOL) of participants during the 1 year of double-blind follow-up. OBJECTIVES: To determine whether QOL improved more in the transplant group than in the sham surgery group and to investigate outcomes at 1 year based on perceived treatment (the type of surgery patients thought they received). DESIGN: Participants were randomly assigned to receive either the transplant or sham surgery. Reported results are from the 1-year double-blind period. SETTING: Participants were recruited from across the United States and Canada. Assessment and surgery were conducted at 2 separate university medical centers. PARTICIPANTS: A volunteer sample of 40 persons with idiopathic Parkinson's disease participated in the transplant ("parent") study, and 30 agreed to participate in the related QOL study: 12 received the transplant and 18 received sham surgery. INTERVENTIONS: Interventions in the parent study were transplantation and sham brain surgery. Assessments of QOL were made at baseline and 4, 8, and 12 months after surgery. MAIN OUTCOME MEASURES: Comparison of the actual transplant and sham surgery groups and the perceived treatment groups on QOL and medical outcomes. We also investigated change over time. RESULTS: There were 2 differences or changes over time in the transplant and sham surgery groups. Based on perceived treatment, or treatment patients thought they received, there were numerous differences and changes over time. In all cases, those who thought they received the transplant reported better scores. Blind ratings by medical staff showed similar results. CONCLUSIONS: The placebo effect was very strong in this study, demonstrating the value of placebo-controlled surgical trials.

A potential compensatory role for endogenous striatal tyrosine hydroxylase-positive neurons in a nonhuman primate model of Parkinson's disease.

The possibility of enhancing endogenous brain repair following neurological disorders, such as Parkinson's disease (PD), is of considerable recent interest. One such mechanism may exist in the striatum as an upregulated population of tyrosine hydroxylase (TH)-immunoreactive neurons that appear after 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) lesions in nonhuman primates as well as in humans with PD. An intriguing possibility is that these endogenous neurons reflect a compensatory mechanism to mitigate the loss of striatal DA due to progressive destruction of the nigrostriatal pathway. The possibility of enhancing the number and function of this population is attractive; however, it is crucial to gain further information about these cells in order to comprehend more fully their possible therapeutic potential. The current research was designed to investigate the fate of this endogenous population in African green monkeys rendered parkinsonian by MPTP lesions. Specifically, we assessed changes in the numbers of striatal neurons expressing TH at differing stages of the toxin-induced behavioral disability and discovered a close relationship with symptom severity and striatal DA neuron numbers. Increased numbers of striatal TH-positive neurons were associated with MPTP treatment that produced parkinsonian symptoms compared to numbers of these neurons in MPTP-treated asymptomatic animals and untreated controls. Expression of striatal DA neurons peaked at the manifestation of symptoms in mild/moderate animals and remained stable in animals that were severely parkinsonian. Furthermore, in severely debilitated animals that improved after fetal dopaminergic grafts, we discovered a return to control levels of the endogenous population. Taken together, our results further support the concept that this population of DA neurons responds to variations in striatal DA tone and may serve as a compensatory mechanism to restore striatal DA levels in the context of significant depletion. Artificially manipulating this endogenous population could prove beneficial for PD treatment, especially for individuals in early disease stages.

Xenografts of MHC-deficient mouse embryonic mesencephalon improve behavioral recovery in hemiparkinsonian rats.

The limited availability of human embryonic tissue for dopamine cell transplants in Parkinson's patients has led to an increased interest in using xenogeneic donor tissue. Unfortunately, without aggressive immunosuppression, such brain xenografts are rejected by the host immune system. Chronic brain xenograft rejection is largely mediated by helper T cells, which require presentation of xenoantigens by major histocompatability complex (MHC) class II for their activation. We examined survival and function of xenografts of E13 mouse mesencephalon deficient in either MHC class I, class II, or both after transplantation into adult hemiparkinsonian rats without immunosuppression. Recipients received grafts from C57BL/6 mice that were either: 1) wild-type (wt), 2) MHC class I knockout (KO), 3) MHC class II KO, 4) MHC class I and II double KO, or 5) saline sham transplants. At 6 weeks after transplantation, recipients of MHC class I KO, class II KO, and double KO xenografts significantly reduced methamphetamine-induced circling rate while rats with wt xenografts and sham-operated rats showed no improvement. MHC class II KO grafts had the greatest number of surviving dopamine neurons. All transplants, including saline sham controls, contained infiltrating host MHC class II-positive cells. Saline sham grafts and MHC class II KO xenografts contained significantly fewer infiltrating host MHC class II-positive cells than did wt grafts. Our results show that MHC class II-deficient xenografts survive transplantation for at least 6 weeks in the absence of immunosuppression, reduce rotational asymmetry, and provoke lesser immune reaction than wt grafts.

Hydrogel formulation determines cell fate of fetal and adult neural progenitor cells.

Hydrogels provide a unique tool for neural tissue engineering. These materials can be customized for certain functions, i.e. to provide cell/drug delivery or act as a physical scaffold. Unfortunately, hydrogel complexities can negatively impact their biocompatibility, resulting in unintended consequences. These adverse effects may be combated with a better understanding of hydrogel chemical, physical, and mechanical properties, and how these properties affect encapsulated neural cells. We defined the polymerization and degradation rates and compressive moduli of 25 hydrogels formulated from different concentrations of hyaluronic acid (HA) and poly(ethylene glycol) (PEG). Changes in compressive modulus were driven primarily by the HA concentration. The in vitro biocompatibility of fetal-derived (fNPC) and adult-derived (aNPC) neural progenitor cells was dependent on hydrogel formulation. Acute survival of fNPC benefited from hydrogel encapsulation. NPC differentiation was divergent: fNPC differentiated into mostly glial cells, compared with neuronal differentiation of aNPC. Differentiation was influenced in part by the hydrogel mechanical properties. This study indicates that there can be a wide range of HA and PEG hydrogels compatible with NPC. Additionally, this is the first study comparing hydrogel encapsulation of NPC derived from different aged sources, with data suggesting that fNPC and aNPC respond dissimilarly within the same hydrogel formulation.

Building biocompatible hydrogels for tissue engineering of the brain and spinal cord.

Tissue engineering strategies employing biomaterials have made great progress in the last few decades. However, the tissues of the brain and spinal cord pose unique challenges due to a separate immune system and their nature as soft tissue. Because of this, neural tissue engineering for the brain and spinal cord may require re-establishing biocompatibility and functionality of biomaterials that have previously been successful for tissue engineering in the body. The goal of this review is to briefly describe the distinctive properties of the central nervous system, specifically the neuroimmune response, and to describe the factors which contribute to building polymer hydrogels compatible with this tissue. These factors include polymer chemistry, polymerization and degradation, and the physical and mechanical properties of the hydrogel. By understanding the necessities in making hydrogels biocompatible with tissue of the brain and spinal cord, tissue engineers can then functionalize these materials for repairing and replacing tissue in the central nervous system.

Defining and designing polymers and hydrogels for neural tissue engineering.

The use of biomaterials, such as hydrogels, as neural cell delivery devices is becoming more common in areas of research such as stroke, traumatic brain injury, and spinal cord injury. When reviewing the available research there is some ambiguity in the type of materials used and results are often at odds. This review aims to provide the neuroscience community who may not be familiar with fundamental concepts of hydrogel construction, with basic information that would pertain to neural tissue applications, and to describe the use of hydrogels as cell and drug delivery devices. We will illustrate some of the many tunable properties of hydrogels and the importance of these properties in obtaining reliable and consistent results. It is our hope that this review promotes creative ideas for ways that hydrogels could be adapted and employed for the treatment of a broad range of neurological disorders.

Modulating cognitive deficits and tau accumulation in a mouse model of aging Down syndrome through neonatal implantation of neural progenitor cells.

Although Down syndrome (DS) is primarily considered as a pediatric disorder, all DS patients incur Alzheimer's disease (AD)-like pathology and about 60% develop an additional AD-like dementia by 30-40 years of age. Cognitive and neuroanatomical changes in DS are least compromised perinatally, indicating there may be an opportunity to modulate their cognitive and neuroanatomical development during aging, preventing or postponing the onset of AD. To this end, neural progenitor cells (NPC) or saline were implanted into the hippocampus of neonatal DS-modeling (trisomic Ts65Dn) mice and non-DS (disomic Ts65Dn) age-matched mice. Twelve months later, implanted and unimplanted mice were assessed for long-term survival of NPC, for cognitive function, hippocampal cell density, and the presence of extracellular tau accumulation. Implantation of NPC in trisomic mice improved learning and memory as assessed by conditioned taste aversion testing, but not on the novel object recognition task. Trisomic mice given saline control injections improved performance on both cognitive tasks compared to unimplanted trisomic mice. In contrast, disomic mice, implanted with either saline or NPC, were impaired in both tasks. Long-term surviving NPC were found in 7 out of 11 disomic brains and 4 out of 5 trisomic brains, with an average survival rate of 3.1% and 5.9% respectively. Extracellular tau aggregations were elevated in trisomic mice, but implantation with NPC was associated with significantly fewer aggregations. This was also seen in disomic mice. Saline injections significantly elevated tau presence in both karyotypes. Based on these results, we conclude that the modest effects of a few surviving NPC cannot be distinguished from those induced by the implant procedure. However, the changes prompted by neonatal treatment were detectable in aged animals. Collectively, our data are consistent with the hypothesis that neonatal therapeutic intervention in DS has the potential to exert positive lasting effects in the later stages of life but that NPC or the implantation approach may not be the most effective strategy and alternative stem cell types or delivery systems merit further investigation.

Effects of neonatal neural progenitor cell implantation on adult neuroanatomy and cognition in the Ts65Dn model of Down syndrome.

As much of the aberrant neural development in Down syndrome (DS) occurs postnatally, an early opportunity exists to intervene and influence life-long cognitive development. Recent success using neural progenitor cells (NPC) in models of adult neurodegeneration indicate such therapy may be a viable option in diseases such as DS. Murine NPC (mNPC, C17.2 cell line) or saline were implanted bilaterally into the dorsal hippocampus of postnatal day 2 (PND 2) Ts65Dn pups to explore the feasibility of early postnatal treatment in this mouse model of DS. Disomic littermates provided karyotype controls for trisomic pups. Pups were monitored for developmental milestone achievement, and then underwent adult behavior testing at 14 weeks of age. We found that implanted mNPC survived into adulthood and migrated beyond the implant site in both karyotypes. The implantation of mNPC resulted in a significant increase in the density of dentate granule cells. However, mNPC implantation did not elicit cognitive changes in trisomic mice either neonatally or in adulthood. To the best of our knowledge, these results constitute the first assessment of mNPC as an early intervention on cognitive ability in a DS model.

The administration of BDNF and GDNF to the brain via PLGA microparticles patterned within a degradable PEG-based hydrogel: Protein distribution and the glial response.

Tailored delivery of neurotrophic factors (NFs) is a critical challenge that continues to inhibit strategies for guidance of axonal growth in vivo. Of particular importance is the ability to recreate innervation of distant brain regions by transplant tissue, for instance rebuilding the nigrostriatal track, one focus in Parkinson's disease research. Many strategies have utilized polymer drug delivery to target NF release in space and time, but combinatorial approaches are needed to deliver multiple NFs at relevant therapeutic times and locations without toxic side effects. Here we engineered a paradigm of PLGA microparticles entrapped within a degradable PEG-based hydrogel device to locally release two different types of NFs with two different release profiles. Hydrogel/microparticle devices were developed and analyzed for their ability to release GDNF in the caudal area of the brain, near the substantia nigra, or BDNF in the rostral area, near the striatum. The devices delivered their respective NFs in a region localized to within 100 µm of the bridge, but not exclusively to the targeted rostral or caudal ends. BDNF was slowly released over a 56-day period, whereas a bolus of GDNF was released around 28 days. The timed delivery of NFs from implanted devices significantly reduced the microglial response relative to sham surgeries. Given the coordinated drug delivery ability and reduced localized inflammatory response, this multifaceted PEG hydrogel/PLGA microparticle strategy may be a useful tool for further development in combining tissue engineering and drug delivery, and recreating the nigrostriatal track.

Impact of degradable macromer content in a poly(ethylene glycol) hydrogel on neural cell metabolic activity, redox state, proliferation, and differentiation.

Hydrogels that degrade at different rates were prepared by copolymerizing slowly degrading macromer poly(ethylene glycol) (PEG) dimethacrylate with a faster degrading macromer poly(lactic acid)-b-PEG-b-poly(lactic acid) dimethacrylate. A clinically relevant population of neural cells composed of differentiated neurons and multipotent precursor cells was cultured within hydrogels. Within 2 h after encapsulation, metabolic activity was higher in hydrogels prepared with increasing levels of degradable content. This improvement was accompanied by a reduction in intracellular redox state and an increase in the fraction of glutathione in the reduced state, both of which persisted throughout 7 days of culture and which may be the result of radical scavenging by lactic acid. Importantly, an increase in cellular proliferation was observed in gels prepared with increasing degradable macromer content after 7 days of growth without a shift in the cellular composition of the culture toward the glial cell phenotype. The findings of this study provide additional insight into the growth of neural cells in PEG-based hydrogels. Results suggest that lactic acid released during gel degradation may impact the function of encapsulated cells, a finding of general interest to biomaterials scientists who focus on the development of degradable polymers for cell culture and drug delivery devices.