Rheological and molecular weight comparisons of approved hyaluronic acid products - preliminary standards for establishing class III medical device equivalence.

Hyaluronic acid of various molecular weights has been in use for the treatment of osteoarthritis knee pain for decades. Worldwide, these products are regulated as either as drugs or devices and in some countries as both. In the US, this class of products is regulated as Class III medical devices, which places specific regulatory requirements on developers of these materials under a Pre-Market Approval process, typically requiring data from prospective randomized controlled clinical studies. In 1984 pharmaceutical manufacturers became able to file an Abbreviated New Drug Application for approval of a generic drug, thus establishing standards for demonstrating equivalence to an existing chemical entity. Recently, the first biosimilar, or 'generic biologic', was approved. Biosimilars are biological products that are approved by the FDA because they are 'highly similar' to a reference product, and have been shown to have no clinically meaningful differences from the reference product. For devices, Class II medical devices have a pathway for declaring equivalence to an existing product by filing a 510 k application for FDA clearance. However, until recently no equivalent regulatory pathway was available to Class III devices. In this paper, we consider the critical mechanical performance parameters for intra-articular hyaluronic products to demonstrate indistinguishable characteristics. Analogous to the aforementioned pathways that allow for a demonstration of equivalence, we examine these parameters for an existing, marketed device and compare molecular weight and rheological properties of multiple batches of a similar product. We propose that this establishes a scientific rationale for establishing Class III medical device equivalence.

Hydraulic responses to environmental perturbations in Tsuga canadensis and Betula lenta.

Eastern hemlock (Tsuga canadensis (L). Carr.) is a late-successional species found across the northeastern United States of America that is currently threatened by the exotic pest, hemlock woolly adelgid (Adelges tsugae Annand). Because whole-tree physiological characteristics may scale to influence ecosystem processes, we considered whole-tree hydraulic controls in eastern hemlock and the replacement species black birch (Betula lenta L.). Through a series of misting perturbations, whole-tree resistances (R), capacitances (C) and time constants (tau) were determined from time series sap flux data in eastern hemlock and black birch. Black birch trees responded more rapidly to environmental perturbations than eastern hemlock. Utilizing the step function after applied treatments, whole-tree tau ranged between 9.4 and 24.8 min in eastern hemlock trees compared with 5.9 to 10.5 min in black birch. Species was not a significant predictor of R or C when controlling for tree size. In both species, R decreased with sapwood area and C increased. Our tau results indicate that the loss and replacement of eastern hemlock by black birch will decrease the lag between transpiration and absorption of water from the soil and potentially alter the diurnal pattern of carbon and water uptake.

Water use and carbon exchange of red oak- and eastern hemlock-dominated forests in the northeastern USA: implications for ecosystem-level effects of hemlock woolly adelgid.

Water use and carbon exchange of a red oak-dominated (Quercus rubra L.) forest and an eastern hemlock-dominated (Tsuga canadensis L.) forest, each located within the Harvard Forest in north-central Massachusetts, were measured for 2 years by the eddy flux method. Water use by the red oak forest reached 4 mm day(-1), compared to a maximum of 2 mm day(-1) by the eastern hemlock forest. Maximal carbon (C) uptake rate was also higher in the red oak forest than in the eastern hemlock forest (about 25 versus 15 micromol m(-2) s(-1)). Sap flux measurements indicated that transpiration of red oak, and also of black birch (Betula lenta L.), which frequently replaces eastern hemlock killed by hemlock woolly adelgid (Adelges tsugae Annand.), were almost twice that of eastern hemlock. Despite the difference between species in maximum summertime C assimilation rate, annual C storage of the eastern hemlock forest almost equaled that of the red oak forest because of net C uptake by eastern hemlock during unusually warm fall and spring weather, and a near-zero C balance during the winter. Thus, the effect on C storage of replacing eastern hemlock forest with a forest dominated by deciduous species is unclear. Carbon storage by eastern hemlock forests during fall, winter and spring is likely to increase in the event of climate warming, although this may be offset by C loss during hotter summers. Our results indicate that, although forest water use will decrease immediately following eastern hemlock mortality due to the hemlock woolly adelgid, the replacement of eastern hemlock by deciduous species such as red oak will likely increase summertime water use over current rates in areas where hemlock is a major forest species.

Interspecific variation in nighttime transpiration and stomatal conductance in a mixed New England deciduous forest.

Transpiration is generally assumed to be insignificant at night when stomata close in response to the lack of photosynthetically active radiation. However, there is increasing evidence that the stomata of some species remain open at night, which would allow for nighttime transpiration if there were a sufficient environmental driving force. We examined nighttime water use in co-occurring species in a mixed deciduous stand at Harvard Forest, MA, using whole-tree and leaf-level measurements. Diurnal whole-tree water use was monitored continuously with Granier-style sap flux sensors in paper birch (Betula papyrifera Marsh.), red oak (Quercus rubra L.) and red maple (Acer rubrum L.). An analysis was conducted in which nighttime water flux could be partitioned between refilling of internal water stores and transpiration. Substantial nighttime sap flux was observed in all species and much of this flux was attributed to the refilling of depleted water stores. However, in paper birch, nighttime sap flux frequently exceeded recharge estimates. Over 10% of the total daily sap flux during the growing season was due to transpiration at night in paper birch. Nighttime sap flux was over 8% of the total daily flux in red oak and 2% in red maple; however, this flux was mainly associated with recharge. On nights with elevated vapor pressure deficit, sap flux continued through the night in paper birch, whereas it reached zero during the night in red oak and red maple. Measurements of leaf-level gas exchange on a night with elevated vapor pressure deficit showed stomatal conductance dropping by only 25% in paper birch, while approaching zero in red oak and red maple. The study highlighted differences in ecophysiological controls on sap flux exerted by co-occurring species. Paper birch is a fast-growing, shade-intolerant species with an earlier successional status than red oak and red maple. Risking water loss through nighttime transpiration may provide paper birch with an ecological advantage by enabling the species to maximize photosynthesis and support rapid growth. Nighttime transpiration may also be a mechanism for delivering oxygen to respiring cells in the deep sapwood of paper birch.