Histological and Immunohistochemical Analysis of the Effects of Topical Melatonin Treatment Associated with Collagen Sponge and rhBMP-2 Protein on Bone Remodeling.

Extensive bone defect healing is an important health issue not yet completely resolved. Different alternative treatments have been proposed but, in face of a critical bone defect, it is still very difficult to reach a complete regeneration, with the new-formed bone presenting all morphological and physiological characteristics of a normal, preinjury bone. Topical melatonin use has shown as a promising adjuvant for bone regeneration due to its positive effects on bone metabolism. Thus, to search for new, safe, biological techniques that promote bone repair and favor defect healing, we hypothesized that there is a synergistic effect of melatonin treatment associated with rhBMP-2 to guide bone regeneration. This study aimed to investigate bone repair effects of topical melatonin administration in different concentrations (1, 10, and 100 µg), associated or not with rhBMP-2. Surgical-induced bone defect healing was qualitatively evaluated through histopathological analysis by light microscopy. Additionally, quantitative stereology was performed in immunohistochemistry-prepared tissue to identify angiogenic, osteogenic, and osteoclastogenic factors. Quantification data were compared between groups by the ANOVA/Tukey test and differences were considered significant when p < 0.05. Our results showed that the presence of the scaffold in the bone defect hindered the process of bone repair because in the group treated with "blood clot + scaffold" the results of bone formation and immunolabeling were reduced in comparison with all other groups (treated with melatonin alone or in association with rhBMP-2). Statistical analysis revealed a significant difference between the control group (bone defect + blood clot), and groups treated with different concentrations of melatonin in association with rhBMP-2, indicating a positive effect of the association for bone repair. This treatment is promising once it becomes a new safe alternative technique for the clinical treatment of fractures, bone defects, and bone grafts. Our results support the hypothesis of the safe use of the association of melatonin and rhBMP-2 and have established a safe and effective dose for this experimental treatment.

Policies and Resources Identified by Youth as Being Important to Prepare for Caregiving Responsibilities.

BACKGROUND: Youth are increasingly upholding significant caregiving responsibilities. These caregiving responsibilities can have emotional, educational, and professional impacts on youth and young adults. And yet, policies and resources focus on adult caregivers and are limited in supporting young caregivers. The purpose of this study was to describe the different types of support that youth identify as being important to prepare to take care of an adult relative. METHODS: We conducted an open-ended, text-message based poll of youth ages 14 to 24 in August 2020. We conducted a content analysis to categorize and describe the different types of support respondents identified in their responses. We compared types of support identified by age-group, gender identity, and prior caregiving experience. RESULTS: Most respondents (42.2%) identified education (eg, skills training) as being an important resource. Other types of support reported included financial support (eg, assistive programs), workplace policies (eg, paid leave), mental health support, and professional support. DISCUSSION: Policy makers should extend existing policies (eg, Family and Medical Leave Act) to include and consider the circumstances of youth and young adults. Policies enabling young caregivers to actively participate in their adult relative's health care visits could be critical to preparing youth for the skills required and the physical and emotional demands associated with caregiving. Coordinated efforts between health and education systems could support youth in learning information about caregiving, medical decision making, and medical tasks.

Development and femoral growth of rabbits of the New Zealand line / Desarrollo y crecimiento femoral de conejas de la línea new zealand

RESUMEN En este proyecto se investigan los cambios que acontecen en el desarrollo y crecimiento de conejos hembras de la línea New Zealand (CoNZ) en sus huesos femorales. Los animales fueron mantenidas en jaulas individuales desde las dos semanas de edad, con comida y agua ad libitum y se sacrificaron en tiempos mensualmente consecutivos: 1, 2, 3, 4, 5, y 6 meses. Tras la obtención de las piezas femorales, y a partir de estudios imagenológicos se determinaron los ángulos del cuello femoral (Af), la longitud total (L), la densidad mineral ósea total, del centro óseo y de la metáfisis femoral (DMOt, DMOco y DMOmf respectivamente), analizándose las variaciones intergrupales por el test Wilcoxon, y corrección de Bonferroni. Se realizaron estudios histológicos de los cortes descalcificados de las piezas femorales. Los análisis sobre los Af mostraron un incremento significativo durante el primer mes mientras que L se estabilizó a partir del 4to mes. Los valores de DMOt mostraron un plateau a partir del cuarto mes, si bien las DMOco y DMOmf ya a partir del tercer mes no mostraron incrementos significativos. Histológicamente se observó para el cuarto mes ausencia de las diferentes zonas características del cartílago de crecimiento metafisiario, con presencia únicamente de un pequeño remanente de células condrales. Desde el quinto mes se observa ausencia total de cartílago, con presencia únicamente de tejido osteoide (TO). La interpretación integrada de los resultados nos permite afirmar, que a partir del cuarto mes de desarrollo, el fémur de CoNZ adquiere características compatibles con un periodo de adultez.

ABSTRACT In this project we investigated the changes of femoral development and growth of female New Zealand rabbits (NZr). Animals were maintained in individual cages since they were two weeks old with food and water ad libitum, and were sacrificed monthly consecutively: 1, 2, 3, 4, 5 and 6. Radiological studies were made with femoral pieces to determine femoral neck angle (fnA), total length (L), total bone mineral density (tBMD), bone center mineral density (bcBMD) and femoral metaphysis bone mineral density (fmBMD). We analyzed intergroup variations with Wilcoxon test and Bonferroni correction. We also performed histologic studies with femoral pieces. The fnA analyzes showed a significant increase in the first month while L stabilized since the fourth month. tBMD showed a plateu since the fourth month, even though bcBMD and fmBMD did not show any significant changes since the third month. In histology it was observed the absence of all typical growth cartilage zones since the fourth month, with the only presence of small remaining cartilage cells. In the fifth month we observed complete absence of cartilage, and presence of osteoid tissue only. The integrated interpretation of the results allows us to affirm that since the fourth month of development the femur of NZr acquires characteristics compatible with the adulthood.

Evaluation of tissue in repair with natural latex and / or hyaluronic acid in surgical bone defects.

This study evaluated the bone repair in surgical defects of rats treated with hyaluronic acid (HA) associated or not with Hevea brasiliensis fraction protein (F-1). Bone defect were created in 15 albino Wistar rats divided into 3 groups (n=5): Control group (1) - blood clot; HA group (2) - 0.5% hyaluronic acid; HAF1 group (3) - 0.1% F-1 protein fraction dissolved in 0.5% hyaluronic acid. After 4 weeks, the animals were euthanized and the bone repair was evaluated through histomorphometric analysis, zymography and immunohistochemistry. The neoformed bone area did not show a significant difference (p = 0.757), but there was a tendency for bone trabeculation to increase in the groups HA and HAF1. For immunohistochemically analysis, there was a difference in vascular endothelial growth factor (VEGF) labeling (p = 0.023), being higher in the groups HA and HAF1 than the control group. No significant difference in bone sialoprotein (BSP) (p = 0.681), osteocalcin (p = 0.954), however, significant difference in platelet endothelial cell adhesion molecule-1 (CD-31) (p = 0.040), with HAF1 group being significantly lower than the control. For zymographic analysis, there was no significant difference for metalloproteinase-2 (MMP-2) (p = 0.068), but there was a tendency to increase MMP-2 in the HA group. Despite the influence on angiogenic factors and the apparent tendency for greater trabeculation in the HA and HAF1 groups, there was no significant difference in the area of ​​newly formed bone tissue in the analyzed period.

Evaluation of tissue in repair with natural latex and / or hyaluronic acid in surgical bone defects

Abstract This study evaluated the bone repair in surgical defects of rats treated with hyaluronic acid (HA) associated or not with Hevea brasiliensis fraction protein (F-1). Bone defect were created in 15 albino Wistar rats divided into 3 groups (n=5): Control group (1) - blood clot; HA group (2) - 0.5% hyaluronic acid; HAF1 group (3) - 0.1% F-1 protein fraction dissolved in 0.5% hyaluronic acid. After 4 weeks, the animals were euthanized and the bone repair was evaluated through histomorphometric analysis, zymography and immunohistochemistry. The neoformed bone area did not show a significant difference (p = 0.757), but there was a tendency for bone trabeculation to increase in the groups HA and HAF1. For immunohistochemically analysis, there was a difference in vascular endothelial growth factor (VEGF) labeling (p = 0.023), being higher in the groups HA and HAF1 than the control group. No significant difference in bone sialoprotein (BSP) (p = 0.681), osteocalcin (p = 0.954), however, significant difference in platelet endothelial cell adhesion molecule-1 (CD-31) (p = 0.040), with HAF1 group being significantly lower than the control. For zymographic analysis, there was no significant difference for metalloproteinase-2 (MMP-2) (p = 0.068), but there was a tendency to increase MMP-2 in the HA group. Despite the influence on angiogenic factors and the apparent tendency for greater trabeculation in the HA and HAF1 groups, there was no significant difference in the area of ​​newly formed bone tissue in the analyzed period.

Resumo Este estudo avaliou o reparo ósseo em defeitos cirúrgicos de ratos tratados com ácido hialurônico (AH) associado ou não à fração proteica de Hevea brasiliensis (F-1). Foram criados defeitos ósseos em 15 ratos albinos Wistar divididos em 3 grupos (n = 5): Grupo controle (1) - coágulo sanguíneo; Grupo HA (2) - ácido hialurônico 0,5%; Grupo HAF1 (3) - fração proteica F-1 0,1% dissolvida em ácido hialurônico a 0,5%. Após 4 semanas, os animais foram submetidos à eutanásia e o reparo ósseo avaliado por meio de análise histomorfométrica, zimografia e imunohistoquímica. A área óssea neoformada não apresentou diferença significativa (p = 0,757), mas houve tendência de aumento da trabeculação óssea nos grupos HA e HAF1. Para a análise imunoistoquímica, houve diferença na marcação do fator de crescimento endotelial vascular (VEGF) (p = 0,023), sendo maior nos grupos HA e HAF1 do que no grupo controle. Nenhuma diferença significativa na sialoproteína óssea (BSP) (p = 0,681), osteocalcina (p = 0,954), no entanto, diferenças significativas foram encontradas para a molécula de adesão de células endoteliais plaquetárias-1 (CD-31) (p = 0,040), com o grupo HAF1 sendo significativamente inferior ao controle. Para a análise zimográfica, não houve diferença significativa para metaloproteinase-2 (MMP-2) (p = 0,068), mas houve tendência de aumento da MMP-2 no grupo HA. Apesar da influência sobre os fatores angiogênicos e da aparente tendência de maior trabeculação nos grupos HA e HAF1, não houve diferença significativa na área de tecido ósseo neoformado no período analisado.

Family members' perspectives on learning cognitively unimpaired older adults' amyloid-ß PET scan results.

BACKGROUND/OBJECTIVES: Disclosure of Alzheimer's disease (AD) risk information to cognitively unimpaired older adults may become more common if preclinical AD is shown to be identifiable and amenable to treatment. Little, however, is known about how families will react to this information. DESIGN AND SETTING: Semi-structured telephonic interviews. PARTICIPANTS: Seventy study partners (mean age = 68 [±11]; 50% female; 70% spouses/significant others; 18% children, siblings; 12% friends) of cognitively unimpaired adults who learned a personalized AD dementia risk estimate and an amyloid-ß PET scan result through their participation in preclinical AD research. MEASUREMENT: Interviewees were asked about their desire for information regarding their family member's AD dementia risk, baseline expectations of risk, understanding of amyloid-ß PET scan results, and the impact of AD dementia risk information on emotions, health behaviors, and future plans, as well as on perceptions of their family member's or friend's memory. RESULTS: Interviewees generally understood the AD dementia risk information (83%) and considered it valuable (75%). Risk information perceived as favorable elicited feelings of happiness and relief; unfavorable information elicited disappointment, as well as increased awareness of the participants' memory and monitoring for incipient changes in cognition. While noting that AD dementia risk information was not medically actionable at this time due to the lack of disease-modifying therapies, some interviewees described changes to their family members' and their own health behaviors and future plans. CONCLUSION: Guidelines for the disclosure of AD dementia risk estimates and biomarker results to cognitively unimpaired adults should account for the needs and interests of individuals and their family members, who may step into a pre-caregiver role.

Special Report from the CDC: Readiness to surge: State health departments' workforce infrastructure during the opioid crisis.

INTRODUCTION: As part of scaling up the response to the opioid overdose epidemic, there is an opportunity to examine how state public health departments addressed workforce and other infrastructure needs to implement a large-scale opioid overdose prevention program. Understanding how this was done-and any lessons learned from the process-can inform future workforce development and capital improvement efforts. METHODS: Administrative data from the Centers for Disease Control and Prevention (CDC) Prescription Drug Overdose Prevention for States (PfS) program were analyzed to understand how states adapted to this emerging public health priority. RESULTS: Six months into the first year of funding, 6 of the 16 state health departments had filled all anticipated staffing positions. States faced challenges obtaining timely expenditure authority and hiring staff. However, states were able to overcome these challenges by strategically reassigning staff, hiring from within, and utilizing existing contract mechanisms. CONCLUSION: Our analysis revealed how planning, using existing infrastructure, and maintaining a prepared workforce are critical to ensure that public health agencies have the ability to surge to meet emerging challenges and effectively utilize resources to achieve program goals. practical applications: Greater attention should be directed toward strategically addressing known barriers and timelines in work plans and budgets during the application and selection process to ensure implementation readiness.

"If It Needs to be Done, It Needs to be Done": National Survey of Youth Experiences and Perspectives on Caregiving.

PURPOSE: The purpose of this study was to explore youth experiences and perspectives on family caregiving to improve programs and policies that impact the well-being of youth. METHODS: In August 2020, we asked three open-ended questions about current and anticipated caregiving responsibilities, impact, and needs using MyVoice, a national text message poll of youth. Content and thematic analysis was conducted to evaluate qualitative responses. RESULTS: In our sample (n = 1,076), 35% of respondents reported previously or currently providing care for an adult relative either independently or by helping another relative. Participants believed caregiving had or would hinder their educational or career goals and that specific training would better prepare them to be a caregiver. CONCLUSIONS: The prevalence of youth caregiving may be higher than previous estimates. Healthcare professionals should evaluate youth for caregiving responsibilities and support them in identifying resources or interventions to reduce potential impacts of caregiving burden on health outcomes.

Advances in translational orthopaedic research with species-specific multipotent mesenchymal stromal cells derived from the umbilical cord.

Compliance with current regulations for the development of innovative medicines require the testing of candidate therapies in relevant translational animal models prior to human use. This poses a great challenge when the drug is composed of cells, not only because of the living nature of the active ingredient but also due to its human origin, which can subsequently lead to a xenogeneic response in the animals. Although immunosuppression is a plausible solution, this is not suitable for large animals and may also influence the results of the study by altering mechanisms of action that are, in fact, poorly understood. For this reason, a number of procedures have been developed to isolate homologous species-specific cell types to address preclinical pharmacodynamics, pharmacokinetics and toxicology. In this work, we present and discuss advances in the methodologies for derivation of multipotent Mesenchymal Stromal Cells derived from the umbilical cord, in general, and Wharton's jelly, in particular, from medium to large animals of interest in orthopaedics research, as well as current and potential applications in studies addressing proof of concept and preclinical regulatory aspects.

Correlates of Formal Support Service Use among Dementia Caregivers.

Informal caregivers for persons with dementia frequently report needing assistance, yet formal support service use has been low. To better understand factors associated with service use, correlates of self-reported service use (e.g., support groups, family mediation, family leave, classes/trainings, and respite care) among dementia caregivers were assessed. The National Poll on Healthy Aging conducted a nationally representative web-based survey of adults aged 50-80 (N = 2,131) using Ispos' KnowledgePanel®; 148 reported caregiving for an adult with memory loss [61.5% female; 25% nonwhite, 54.1% aged 50-64]. Multivariable logistic regression analyzes assessed caregiver and care recipient characteristics associated with service use within the prior year. Nearly 25% of caregivers used at least one service. Caregiver characteristics associated with greater likelihood of service use included not working [7.5 OR; 2.73, 20.62 CI]; income <$30,000/year [5.9 OR; 1.27, 27.17 CI]; and residing in Western US [7.5 OR; 2.73, 20.62 CI]. Ability of care recipient to be left alone safely for only three hours or less [5.1 OR; 1.66, 15.46 CI] was associated with greater likelihood of use. Support service use remains low. Findings suggest need to consider caregivers' employment status, income, and geographical location in service design and implementation.

Recombinant Proteins-Based Strategies in Bone Tissue Engineering.

The increase in fracture rates and/or problems associated with missing bones due to accidents or various pathologies generates socio-health problems with a very high impact. Tissue engineering aims to offer some kind of strategy to promote the repair of damaged tissue or its restoration as close as possible to the original tissue. Among the alternatives proposed by this specialty, the development of scaffolds obtained from recombinant proteins is of special importance. Furthermore, science and technology have advanced to obtain recombinant chimera's proteins. This review aims to offer a synthetic description of the latest and most outstanding advances made with these types of scaffolds, particularly emphasizing the main recombinant proteins that can be used to construct scaffolds in their own right, i.e., not only to impregnate them, but also to make scaffolds from their complex structure, with the purpose of being considered in bone regenerative medicine in the near future.

Biological performance of a bioabsorbable Poly (L-Lactic Acid) produced in polymerization unit: in vivo studies.

Background: The biomaterials engineering goal is to manufacture a biocompatible scaffold that adequately supports or improves tissue regeneration after implantation of the biomaterial in the injured area. Many requirements are demanded for a biomaterial, such as biocompatibility, elasticity, degradation time, and a very important factor is its cost of importation or synthesis, making its application inaccessible to some countries. Studies about biomaterials market show that Polylactic acid (PLLA) is one of the most used polymers, but expensive to produce. It becomes important to prove the biocompatibility of the new PLLA and to find strategies to produce biocompatible biopolymers at an acceptable production cost. Methods: In this work, the polylactic acid biomaterial was synthesized by ring-opening polymerization. The polymer was submitted to initial in vivo biocompatibility studies in 12 New Zealand female rabbits, assigned to two groups: (1) Lesion and PLLA group (n = 6), (2) Lesion No PLLA group (n = 6). Each group was divided into two subgroups at six and nine months post-surgical time. Before euthanasia clinical and biochemical studies were performed and after that tomographic (CT), histological (Hematoxylin and Eosin and Masson's trichrome) and histomorphometric analyses were performed to evaluate the injury site and prove biocompatibility. The final cost of this polymer was analyzed. Results: The statistical studies of hemogram and hepatocyte enzymes, showed that there were no significant differences between the groups for any of the times studied, in any of the variables considered and the results of CT and histology showed that there was an important process of neoregeneration. The cost analysis showed the biopolymer synthesis is between R$3,06 - R$5,49 cheaper than the import cost. Conclusions: It was possible to synthesize the PLLA biopolymer by cyclic ring opening, which proved to be biocompatible, potential osteoregenerative and cheaper than other imported biopolymers.

Bone fracture healing: perspectives according to molecular basis.

Fractures have a great impact on health all around the world and with fracture healing optimization; this problem could be resolved partially. To make a practical contribution to this issue, the knowledge of bone tissue, cellularity, and metabolism is essential, especially cytoskeletal architecture and its transformations according to external pressures. Special physical and chemical characteristics of the extracellular matrix (ECM) allow the transmission of mechanical stimuli from outside the cell to the plasmatic membrane. The osteocyte cytoskeleton is conformed by a complex network of actin and microtubules combined with crosslinker proteins like vinculin and fimbrin, connecting and transmitting outside stimuli through EMC to cytoplasm. Herein, critical signaling pathways like Cx43-depending ones, MAPK/ERK, Wnt, YAP/TAZ, Rho-ROCK, and others are activated due to mechanical stimuli, resulting in osteocyte cytoskeletal changes and ECM remodeling, altering the tissue and, therefore, the bone. In recent years, the osteocyte has gained more interest and value in relation to bone homeostasis as a great coordinator of other cell populations, thanks to its unique functions. By integrating the latest advances in relation to intracellular signaling pathways, mechanotransmission system of the osteocyte and bone tissue engineering, there are promising experimental strategies, while some are ready for clinical trials. This work aims to show clearly and precisely the integration between cytoskeleton and main molecular pathways in relation to mechanotransmission mechanism in osteocytes, and the use of this theoretical knowledge in therapeutic tools for bone fracture healing.

Disclosing genetic risk for Alzheimer's dementia to individuals with mild cognitive impairment.

INTRODUCTION: The safety of predicting conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia using apolipoprotein E (APOE) genotyping is unknown. METHODS: We randomized 114 individuals with MCI to receive estimates of 3-year risk of conversion to AD dementia informed by APOE genotyping (disclosure arm) or not (non-disclosure arm) in a non-inferiority clinical trial. Primary outcomes were anxiety and depression scores. Secondary outcomes included other psychological measures. RESULTS: Upper confidence limits for randomization arm differences were 2.3 on the State Trait Anxiety Index and 0.5 on the Geriatric Depression Scale, below non-inferiority margins of 3.3 and 1.0. Moreover, mean scores were lower in the disclosure arm than non-disclosure arm for test-related positive impact (difference: -1.9, indicating more positive feelings) and AD concern (difference: -0.3). DISCUSSION: Providing genetic information to individuals with MCI about imminent risk for AD does not increase risks of anxiety or depression and may provide psychological benefits.

Effectiveness of rhBMP-2 association to autogenous, allogeneic, and heterologous bone grafts.

Proteins with osteoinductive potential, especially recombinant human bone morphogenetic protein (rhBMP)-2, have large effects on cell growth and their differentiation. The aim of this study was to assess repair of bone defects in rat calvaria with different types of grafts associated with rhBMP-2, through immunohistochemistry and micro computed tomography (CT) analyses. A total of 35 male Wistar rats were selected, each weighing ~250 g, with a waiting period of 6 weeks from the creation of the defect to the sacrifice, and divided into five groups (n = 7): autograft plus 5 µg rhBMP-2 (AuG/BMP-2); allograft plus 5 µg rhBMP-2 (AlG/BMP-2); xenograft (heterologous) plus 5 µg rhBMP-2 (XeG/BMP-2); 5 µg rhBMP-2 (BMP-2) and the control group (n = 7). The micro CT reveal that all groups associating different bone grafts with BMP-2 showed increased bone formation compared to the control. The immunostaining show that osteocalcin and bone sialoprotein were higher in groups with BMP-2 than control group; BMP was high expressed in AuG/BMP-2, AlG/BMP-2, and BMP-2; vascular endothelial growth factor (VEGF) was more expressed in groups with BMP-2; VEGF-R2 was low to moderate in AuG/BMP-2, XeG/BMP-2, and BMP-2, predominantly moderate in AlG/BMP-2 and low in the control; CD-31 was predominantly moderate in AuG/BMP-2, AlG/BMP-2, and XeG/BMP-2, low to moderate in BMP-2 and low in the control. The results revealed that rhBMP-2 improved bone repair when administered alone, or when associated with different bone grafts.

MMPs are Involved in Osteoporosis and are Correlated with Cardiovascular Diseases.

Osteoporosis and cardiovascular diseases are common causes of morbidity and mortality worldwide, especially in people aged over 60 years. Osteoporosis is characterized by low bone mineral density, which deteriorates the microarchitecture of bones and increases the risk of bone fractures. Other pathologies also constitute risk factors for the development of osteoporosis, mainly cardiovascular diseases. In fact, a growing number of reports have shown a positive correlation between cardiovascular diseases and low bone mineral density. MMPs are proteases that participate in the organized degradation of the extracellular matrix (ECM) and which play essential physiological roles, such as cardiovascular and bone tissue remodeling. Overexpression of MMPs underlies pathological processes like osteoporosis and cardiovascular diseases. MMP-1, -2, -9, -13, and -14 are expressed in bone tissue and are key players in the digestion of bone matrix by osteoblasts. Considering this relationship between osteometabolic and cardiovascular pathologies and MMPs, this review focuses on the involvement of MMPs in osteoporosis and on their participation in cardiovascular diseases; it also deals with the positive correlation between osteoporosis and cardiovascular diseases. Although there are many drugs to treat osteoporosis, controversies exist. Here, we will describe these controversies and will discuss how inhibition of MMPs could be an alternative strategy to or an adjuvant therapy in the current treatment of osteoporosis.

* Bone Regeneration Mediated by a Bioactive and Biodegradable Extracellular Matrix-Like Hydrogel Based on Elastin-Like Recombinamers.

The morbidity of bone fractures and defects is steadily increasing due to changes in the age pyramid. As such, novel biomaterials that are able to promote the healing and regeneration of injured bones are needed to overcome the limitations of auto-, allo-, and xenografts, while providing a ready-to-use product that may help to minimize surgical invasiveness and duration. In this regard, recombinant biomaterials, such as elastin-like recombinamers (ELRs), are very promising as their design can be tailored by genetic engineering, thus allowing scalable production and batch-to-batch consistency, among others. Furthermore, they can self-assemble into physically crosslinked hydrogels above a certain transition temperature, in this case body temperature, but are injectable below this temperature, thereby markedly reducing surgical invasiveness. In this study, we have developed two bioactive hydrogel-forming ELRs, one including the osteogenic and osteoinductive bone morphogenetic protein-2 (BMP-2) and the other the Arg-Gly-Asp (RGD) cell adhesion motif. The combination of these two novel ELRs results in a BMP-2-loaded extracellular matrix-like hydrogel. Moreover, elastase-sensitive domains were included in both ELR molecules, thereby conferring biodegradation as a result of enzymatic cleavage and avoiding the need for scaffold removal after bone regeneration. Both ELRs and their combination showed excellent cytocompatibility, and the culture of cells on RGD-containing ELRs resulted in optimal cell adhesion. In addition, hydrogels based on a mixture of both ELRs were implanted in a pilot study involving a femoral bone injury model in New Zealand white rabbits, showing complete regeneration in six out of seven cases, with the other showing partial closure of the defect. Moreover, bone neoformation was confirmed using different techniques, such as radiography, computed tomography, and histology. This hydrogel system therefore displays significant potential in the regeneration of bone defects, promoting self-regeneration by the surrounding tissue with no involvement of stem cells or osteogenic factors other than BMP-2, which is released in a controlled manner by elastase-mediated cleavage from the ELR backbone.

Boron neutron capture synovectomy (BNCS) as a potential therapy for rheumatoid arthritis: radiobiological studies at RA-1 Nuclear Reactor in a model of antigen-induced arthritis in rabbits.

Rheumatoid arthritis is a chronic autoimmune pathology characterized by the proliferation and inflammation of the synovium. Boron neutron capture synovectomy (BNCS), a binary treatment modality that combines the preferential incorporation of boron carriers to target tissue and neutron irradiation, was proposed to treat the pathological synovium in arthritis. In a previous biodistribution study, we showed the incorporation of therapeutically useful boron concentrations to the pathological synovium in a model of antigen-induced arthritis (AIA) in rabbits, employing two boron compounds approved for their use in humans, i.e., decahydrodecaborate (GB-10) and boronophenylalanine (BPA). The aim of the present study was to perform low-dose BNCS studies at the RA-1 Nuclear Reactor in the same model. Neutron irradiation was performed post intra-articular administration of BPA or GB-10 to deliver 2.4 or 3.9 Gy, respectively, to synovium (BNCS-AIA). AIA and healthy animals (no AIA) were used as controls. The animals were followed clinically for 2 months. At that time, biochemical, magnetic resonance imaging (MRI) and histological studies were performed. BNCS-AIA animals did not show any toxic effects, swelling or pain on palpation. In BNCS-AIA, the post-treatment levels of TNF-α decreased in four of six rabbits and IFN-γ levels decreased in five of six rabbits. In all cases, MRI images of the knee joint in BNCS-AIA resembled those of no AIA, with no necrosis or periarticular effusion. Synovial membranes of BNCS-AIA were histologically similar to no AIA. BPA-BNCS and GB-10-BNCS, even at low doses, would be therapeutically useful for the local treatment of rheumatoid arthritis.