Biomaterials been performed which combine PNIPAM and

Biomaterials
are any material that is used to treat, augment, or replace a tissue, organ, or
function of the body 1,2. In drug delivery applications, these biomaterials
should ideally be biocompatible, of high mechanical integrity, and capable of precisely
regulating both spatial and temporal delivery of one or more bioactive elements
3.  Over the
past few decades, one unique class of biomaterials that have garnered keen
interest in drug delivery applications are hydrogels. Hydrogels are
three-dimensional, crosslinked networks which when polymerized, form a highly
porous matrix whose interstitial space can be filled with water or other
aqueous solutions, while remaining insoluble, allowing for effective
immobilization and release of active agents and biomolecules 4–6. Hydrogels can be formed from any water-soluble
polymer, some of which have the ability to respond to changes in environmental
stimuli, such as changes in temperature, pH, or magnetic force 7,8. Of this subset of biomaterials, often referred to
as smart materials, thermoresponsive polymers are the most widely investigated,
due to their reversible phase (or volume) transition that occurs in response to
changes in temperature. Poly(N-isopropylacrylamide)
(PNIPAM) is an extensively researched thermoresponsive polymers in drug
delivery due to its physiologically relevant lower critical solution
temperature (LCST) (~32°C). Below its LCST, PNIPAM is in its hydrophilic coil
state, absorbing water. As the temperature is increased, the polymer
transitions to a hydrophobic globular state, expelling water molecules out of
the polymer network 9–13. Studies have shown the versatility of PNIPAM
hydrogels through altering the matrix’s pore size to alter loading capacities
and delivery rates, however; as is the case with most synthetic polymers, PNIPAM
is not generally not cell adhesive without modification 14–17.

To
improve the bioactive performance of synthetic gels, bioactive molecules such
as peptides or growth factors have been incorporated into synthetic gels to aid
in mediating cell functions, allowing for improved cell growth 18–20. Alternately, synthetic/ natural hybrid polymers
can be created. Natural polymers such as proteins and polysaccharides, provide
an inherently biocompatible, biodegradable matrix that aid in critical
biological functions. Studies have been performed which combine PNIPAM and
natural components, including gelatin, chitosan, styrene, hyaluronic acid,
cellulose, and polyamino acids 21–28. Collagen is a major structural protein in the
extracellular matrix (ECM) which promotes cell adhesion via integrin specific
binding sites (?1?1, ?2?1, ?10?1)
29–32. However, pure collagen hydrogels have relatively
poor mechanical properties at physiological mass fractions 15. Hence, combining these different materials may
allow for one or more of the desired tissue properties to be mimicked,
resulting in an optimize, tunable drug delivery system. Despite the clear
advantages of the integration collagen into these polymer systems minimal
hybrid hydrogels have been produced with explore PNIPAM in combination with collagen.
Currently, studies have been produced which explore the mechanical properties
and cytocompatibility of collagen in hybrid PNIPAM-styrene hydrogels; however,
these materials have not been synthesized with pure PNIPAM and focus more on
point of use tissue engineering applications, therefore lacking model drug
delivery experimentation  33. PNIPAM grafted to collagen fibrils has also been
shown to provide a viable environment for cells, but cells remained a rounded
morphology 34.

Therefore,
it was the goal of this work to fabricate hybrid PNIPAM: collagen hydrogels and
investigate the effects of variable composition on: (1) hydrogel’s microscale
structure, (2) temperature-dependent syneresis, (3) model drug release
kinetics, and (4) cytotoxicity. We observed that as the mass ratio of collagen
was modified, the resultant hydrogel structure, syneresis, drug release
profile, and cytocompatibility could be successfully tuned. 

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