CineCT platform for in vivo and ex vivo measurement of 3D high resolution Lagrangian strains in the left ventricle following myocardial infarction and intramyocardial delivery of theranostic hydrogel.

Myocardial infarction (MI) produces acute changes in strain and stiffness within the infarct that can affect remote areas of the left ventricle (LV) and drive pathological remodeling. We hypothesized that intramyocardial delivery of a hydrogel within the MI region would lower wall stress and reduce adverse remodeling in Yorkshire pigs (n = 5). 99mTc-Tetrofosmin SPECT imaging defined the location and geometry of induced MI and border regions in pigs, and in vivo and ex vivo contrast cine computed tomography (cineCT) quantified deformations of the LV myocardium. Serial in vivo cineCT imaging provided data in hearts from control pigs (n = 3) and data from pigs (n = 5) under baseline conditions before MI induction, post-MI day 3, post-MI day 7, and one hour after intramyocardial delivery of a hyaluronic acid (HA)-based hydrogel with shear-thinning and self-healing properties to the central infarct area. Isolated, excised hearts underwent similar cineCT imaging using an ex vivo perfused heart preparation with cyclic LV pressurization. Deformations were evaluated using nonlinear image registration of cineCT volumes between end-diastole (ED) and end-systole (ES), and 3D Lagrangian strains were calculated from the displacement gradients. Post-MI day 3, radial, circumferential, maximum principal, and shear strains were reduced within the MI region (p < 0.04) but were unchanged in normal regions (p > 0.6), and LV end diastolic volume (LV EDV) increased (p = 0.004), while ejection fraction (EF) and stroke volume (SV) decreased (p < 0.02). Post-MI day 7, radial strains in MI border zones increased (p = 0.04) and dilation of LV EDV continued (p = 0.052). There was a significant negative linear correlation between regional radial and maximum principal/shear strains and percent infarcted tissue in all hearts (R2 > 0.47, p < 0.004), indicating that cineCT strain measures could predict MI location and degree of injury. Post-hydrogel day 7 post-MI, LV EDV was significantly reduced (p = 0.009), EF increased (p = 0.048), and radial (p = 0.021), maximum principal (p = 0.051), and shear strain (p = 0.047) increased within regions bordering the infarct. A smaller strain improvement within the infarct and normal regions was also noted on average along with an improvement in SV in 4 out of 5 hearts. CineCT provides a reliable method to assess regional changes in strains post-MI and the therapeutic effects of intramyocardial hydrogel delivery.

A definition of bioinks and their distinction from biomaterial inks.

Biofabrication aims to fabricate biologically functional products through bioprinting or bioassembly (Groll et al 2016 Biofabrication 8 013001). In biofabrication processes, cells are positioned at defined coordinates in three-dimensional space using automated and computer controlled techniques (Moroni et al 2018 Trends Biotechnol. 36 384-402), usually with the aid of biomaterials that are either (i) directly processed with the cells as suspensions/dispersions, (ii) deposited simultaneously in a separate printing process, or (iii) used as a transient support material. Materials that are suited for biofabrication are often referred to as bioinks and have become an important area of research within the field. In view of this special issue on bioinks, we aim herein to briefly summarize the historic evolution of this term within the field of biofabrication. Furthermore, we propose a simple but general definition of bioinks, and clarify its distinction from biomaterial inks.

Recent advances in hydrogels for cartilage tissue engineering.

Articular cartilage is a load-bearing tissue that lines the surface of bones in diarthrodial joints. Unfortunately, this avascular tissue has a limited capacity for intrinsic repair. Treatment options for articular cartilage defects include microfracture and arthroplasty; however, these strategies fail to generate tissue that adequately restores damaged cartilage. Limitations of current treatments for cartilage defects have prompted the field of cartilage tissue engineering, which seeks to integrate engineering and biological principles to promote the growth of new cartilage to replace damaged tissue. To date, a wide range of scaffolds and cell sources have emerged with a focus on recapitulating the microenvironments present during development or in adult tissue, in order to induce the formation of cartilaginous constructs with biochemical and mechanical properties of native tissue. Hydrogels have emerged as a promising scaffold due to the wide range of possible properties and the ability to entrap cells within the material. Towards improving cartilage repair, hydrogel design has advanced in recent years to improve their utility. Some of these advances include the development of improved network crosslinking (e.g. double-networks), new techniques to process hydrogels (e.g. 3D printing) and better incorporation of biological signals (e.g. controlled release). This review summarises these innovative approaches to engineer hydrogels towards cartilage repair, with an eye towards eventual clinical translation.

Ordered, adherent layers of nanofibers enabled by supramolecular interactions.

Aligned nanofibrous substrates can be created by electrospinning, but methods for creating multilamellar structures of aligned fibers are limited. Here, apposed nanofibrous scaffolds with pendant ß-cyclodextrin (CD) were adhered together by adamantane (Ad) modified hyaluronic acid, exploiting the guest-host interactions of CD and Ad for macroscopic assembly. Stable user-defined multi-layered scaffolds were formed for cell culture or tissue engineering.

Macromer density influences mesenchymal stem cell chondrogenesis and maturation in photocrosslinked hyaluronic acid hydrogels.

OBJECTIVE: Engineering cartilage requires that a clinically relevant cell type be situated within a 3D environment that supports cell viability, the production and retention of cartilage-specific extracellular matrix (ECM), and eventually, the establishment of mechanical properties that approach that of the native tissue. In this study, we investigated the ability of bone marrow derived mesenchymal stem cells (MSCs) to undergo chondrogenesis in crosslinked methacrylated hyaluronic acid hydrogels (MeHA) of different macromer concentrations (1, 2, and 5%). DESIGN: Over a 6 week culture period under pro-chondrogenic conditions, we evaluated cartilage-specific gene expression, ECM deposition within constructs and released to the culture media, and mechanical properties in both compression and tension. Further, we examined early matrix assembly and long term histological features of the forming tissues, as well as the ability of macromolecules to diffuse within hydrogels as a function of MeHA macromer concentration. RESULTS: Findings from this study show that variations in macromer density influence MSC chondrogenesis in distinct ways. Increasing HA macromer density promoted chondrogenesis and matrix formation and retention, but yielded functionally inferior constructs due to limited matrix distribution throughout the construct expanse. In 1% MeHA constructs, the equilibrium compressive modulus reached 0.12MPa and s-GAG content reached nearly 3% of the wet weight, values that matched or exceeded those of control agarose constructs and that are 25 and 50% of native tissue levels, respectively. CONCLUSIONS: These data provide new insight into how early matrix deposition regulates long term construct development, and defines new parameters for optimizing the formation of functional MSC-based engineered articular cartilage using HA hydrogels.

An injectable, biodegradable hydrogel for trophic factor delivery enhances axonal rewiring and improves performance after spinal cord injury.

The failure of long descending pathways to regenerate after spinal cord injury (SCI) is generally attributed to inhibitory proteins associated with the glial scar and myelin, or to the loss of neurons' intrinsic capacity to grow, or both. Here, we describe the use of hydrogels as a novel way to deliver molecules that promote axon growth in the injured CNS of adult rats. This method utilizes an injectable liquid polymer solution that crosslinks into a biodegradable, water-swollen hydrogel when photoactivated under visible light. Neurotrophin-3 (NT-3), a trophic factor known to act on corticospinal tract (CST) projection neurons, was used as a prototypic pro-regenerative molecule. Hydrogel release properties were established in vitro to ensure long-term, sustained NT-3 release over a 2-week period; this avoided the need for multiple injections or minipump implantation. Hydrogel/NT-3-treated animals showed improved recovery in the open-field BBB test and in a horizontal ladder walk test compared to controls implanted with hydrogel alone. At the anatomical level, hydrogel/NT-3-treated animals showed far greater axon growth than controls in two major descending pathways for motor control, the CST and the raphespinal tract. In the case of the CST, much of the NT-3-induced growth represented collateral branching from undamaged ventral CST fibers. These studies demonstrate the effectiveness of hydrogel technology as a clinically feasible delivery system to promote regeneration and enhance functional outcome after spinal cord injury.

Conversion and temperature profiles during the photoinitiated polymerization of thick orthopaedic biomaterials.

Polymerization of a tetrafunctional monomer was investigated under a variety of photoinitiation conditions to assess the ability to form thick materials in situ for orthopaedic applications. The major biological concerns include local cell and tissue necrosis due to the polymerization exotherm and low conversions at greater depths due to light attenuation through thick samples. Experimental results indicate that depth of cure and temperature rises are controllable by altering the photoinitiator concentration, initiating light intensity, and type of photoinitiator. For example, no measurable conversion was detected at a 1.0 cm depth when polymerization was initiated with 1.0 wt% DMPA and 100 mW/cm2 ultraviolet light, whereas approximately 40% conversion was obtained when the initiator concentration was lowered to 0.1 wt%. This conversion was further increased to approximately 55% when a photobleaching initiator system was employed. At the highest rate of initiation studied (i.e., 1.0 wt% DMPA irradiated with 100 mW/cm2 ultraviolet light), a maximum temperature of approximately 49 degrees C was reached at the sample surface; however, this temperature dramatically decreased to approximately 33 degrees C when the light intensity was decreased to 25 mW/cm2. Finally, dual initiating systems that synergistically combine the advantages of photoinitiation and thermal initiation were investigated.

In situ forming lactic acid based orthopaedic biomaterials: influence of oligomer chemistry on osteoblast attachment and function.

The ability of osteoblasts to attach and function normally on scaffolds fabricated from synthetic materials is essential for musculoskeletal tissue engineering applications. In this study, the osteoconductivity of polymer networks formed from multifunctional lactic acid oligomers was assessed. These oligomers form highly crosslinked networks via a photoinitiated polymerization, which provides potential advantages for many orthopaedic applications. Depending on the initial oligomer chemistry and the resultant polymer hydrophobicity, protein adsorption and osteoblast function varied significantly between the various lactic acid based polymer chemistries. Results were compared to control polymers of tissue culture polystyrene (TCPS) and 50:50 poly(lactic-co-glycolic acid) (PLGA). The viability of osteoblasts attached to poly(2EG10LA) and poly(2EG6LA) was close to the TCPS and PLGA after 7 and 14 days of culture, whereas cell viability was approximately 50% lower on poly(8EG6LA). Additionally, the alkaline phosphatase activity and mineralization of attached osteoblasts were similar on poly(2EG10LA) and PLGA, whereas these markers of bone formation were significantly lower for poly(2EG6LA) and poly(8EG6LA). For example, the alkaline phosphatase activity of rat calvarial osteoblasts attached to poly(2EG10LA) was 0.048 +/- 0.006 micromol mg(-1) protein-min, but only 0.030 +/- 0.003 micromol mg(-1) protein-min for osteoblasts attached to poly(8EG6LA) after 14 days of culture. Finally, osteoblasts were seeded onto three-dimensional scaffolds to demonstrate the applicability of the scaffolds for bone tissue engineering.

Heredity, color vision, and alcoholism.

Ninety-two Cree individuals were tested with the Farnsworth-Munsell 100-Hue Test (FM = 100). Information concerning racial membership, age, sex, and drinking behavior was collected. High error scores (for the FM-100) were found in this Cree population. Alcoholic individuals (both abstinent and nonabstinent) had higher error scores than a comparable population of nonalcoholic Cree individuals from the same population. Implications concerning the etiology of alcoholism are discussed.

Cardiovascular variability and introversion/extroversion, neuroticism and psychoticism.

Forty-eight subjects were measured during a 10 min rest period for pulse wave velocity (PWV) and heart rate (HR) level and variability, using a Cyborg BL 907 instrument. These subjects were also evaluated by means of the Eysenck Personality Questionnaire for I-E, N, P and L. These data were factor analyzed. Five factors were identified which were accounted for 80.6% of the variance. These factors were: 'cardiovascular lability', 'heart rate time trends', 'cardiovascular balance', 'sex effects' and 'self reports'. The EPQ measurements separated from the physiological measurements in the factor analysis and none were found to be significantly loaded on any physiological variables. On the other hand, significant physiological correlations were found with N. This study adds a possible blood pressure and heart rate descripter to N.

Cosine analysis of heart beat data of children in a stressful situation.

The EKG of twenty-four children (mean age = = 5.7 years) was individually and continuously recorded in a dental situation. Measures of cardiac activity (heart rate [HR] and heart rate variability [HRV]) were computed by means of a CDC 1,700 and an IBM 360 computer. Histograms of heart rate (HR) and heart rate variability (HRV) measures were generated. -Successive cosine fits were fitted for each 70 beats within an interval for each individual and these cosine fits were also presented in a histogram which represented a frequency analysis of cyclic functions within individuals. Within and between subject correlations were also computed for all measures. Sinus arrhythmia seemed to account for less of the variance than a yet unexplained cosine fit function having a lower limit of 18.6 seconds in this child population. In this population many measures of HRV seem to be negatively correlated with HR.

A review of heart-rate variability and evaluation.

A review of the literature concerning heart rate and various forms of heart-rate variability and studies of behavior associated with these variables has been presented. Emphasis has been placed on the apparent discrepancies and inconsistencies reported within the literature as well as major methodological differences which make the integration of the data presented by various researchers almost impossible.