CHEN, Lingyun (- Jasper AvenueEdmonton, Alberta T5J 4P6, 10230, CA)
WANG, Yixiang (- Jasper AvenueEdmonton, Alberta T5J 4P6, 10230, CA)
ENTCHEVA, E. ET AL.: 'Functional cardiac cell constructs on cellulose-based scaffolding' BIOMATERIALS vol. 25, 2004, pages 5753 - 5762, XP004508621
1. A cellulose composite gel comprising a solid phase comprising cellulose nanowhiskers embedded in a cellulose matrix. 2. The gel of claim 1 wherein the solid phase comprises about 5 wt% to about 60 wt% cellulose nanowhiskers.
3. The gel of claim 2 comprising about 20 wt% to about 35 wt% of cellulose nanowhiskers. 4. The gel of claim 2 comprising about 35 wt% to about 50 wt% of cellulose nanowhiskers.
5. The gel of claim 1 further comprising a therapeutic agent dispersed within the gel.
6. A method of forming a cellulose composite gel comprising the steps of:
a) forming an aqueous solvent comprising cellulose, sodium hydroxide, and urea; and dispersing cellulose nanowhiskers in the aqueous solvent to form a suspension;
b) heating the suspension to form a gel; and
c) immersing the gel in water to regenerate the gel. 7. The method of claim 6 wherein the aqueous solvent is formed by cooling a solution of sodium hydroxide and urea and dissolving cellulose into the cooled solution.
8. The method of claim 6 wherein the suspension is heated at a temperature between about 30°C to about 40°C.
9. The method of claim 6 wherein the gel is regenerated with a therapeutic agent, such that the therapeutic agent is dispersed within the regenerated gel.
10. A scaffold for tissue regeneration or wound repair, comprising a composite gel comprising cellulose nanowhiskers embedded in a cellulose matrix.
11. A method of regenerating tissue or repairing a wound comprising the steps of placing a composite gel as claimed in claim 5, carrying a therapeutically effective amount of a therapeutic agent to provide a localized regenerating or repairing effect.
12. A medical device comprising a composite gel as claimed in claim 1 or claim 5.
13. The medical device of claim 12 wherein the gel is coated on the medical device.
14. The medical device of claim 12 wherein the gel is comprised within the medical device.
15. The medical device of claim 12 which is a dressing, substrate or patch.
Field of the Invention  The present invention relates to a composite gel comprising a cellulose matrix and cellulose nanowhiskers dispersed within the matrix, methods for its production, and methods of its use as a scaffold in tissue regeneration or wound repair.
Background of the Invention
 Biomaterials-based scaffolds are of increasing interest in tissue engineering and regenerative medicine since they mimic the characteristics of the extracellular matrix at the nanometer scale and induce natural developmental and/or wound healing processes (Wei et al, 2008). Such hierarchical porous architectures can not only guide neo tissue formation and organization, but also act as nanoscaled drug delivery systems to enhance tissue regeneration capacity (Ma, 2004). Natural polymers are potential candidates for providing optimal scaffolding since they generally have good biocompatibility and biodegradability, as well as reactive groups on their side chains for various modifications to modulate their physico-chemical properties.  Cellulose is a linear homopolymer of glucose (C 6 Hi 0 O 5 )„, and is widely available, inexpensive, and biocompatible. Importantly, it displays mechanical properties matching those of hard and soft tissues (Martson et al, 1999; Miiller et al, 2006). Cellulose derivatives, such as cellulose acetate, hydroxyethylcellulose and sodium carboxymethylcellulose, have been converted into membranes and gels as viscosurgical devices, drug delivery systems, and scaffolds (Andrews et al. , 2005; Fundueanu et al , 2005; Entcheva et al, 2004). However, materials converted directly from cellulose are limited since cellulose is difficult to dissolve and process without chemical modifications.
 Cellulose can be rapidly dissolved in a sodium hydroxide-urea aqueous solution pre-cooled to -12°C through a fast dynamic self-assembly process (Cai et al, 2008). Based on this "green" solvent, cellulose is easily machinable and thus available in a wide range of forms and shapes with various functions (Cai et al, 2007; Qi et al , 2009a; Luo et al , 2009; Chang et al , 2009). Physically cross-linked cellulose gels exhibiting hydrophilicity, solute permeability, and non-toxicity have also shown good mechanical properties and demonstrated potential application in the pharmaceutical area. Such gels were prepared by a freezing-thawing or pre-gelation process which is time-consuming, taking from between eight hours to three weeks, hence unsuitable for industrial production (Chang et al , 2008; Liang et al, 2007; Liang et al , 2008; Wu et al, 2010).  Mild thermal treatment provides a convenient and rapid method to prepare irreversible physically cross-linked cellulose gels based on the sodium hydroxide-urea aqueous system. However, shrinkage occurs when these cellulose gels are immersed and regenerated in a non-solvent bath, leading to the distortion of the final products (Sescousse et al, 2009).  There remains a need in the art for methods for facilitating the efficient formation of cellulose gels having desirable properties. Further, cellulose gels suitable for medical applications are desirable.
Summary of the Invention
 The present invention relates to a composite gel comprising a matrix of cellulose and cellulose nanowhiskers dispersed within the matrix, methods for its production and use as a scaffold tissue regeneration or wound repair.
 In one aspect, the invention comprises a cellulose composite gel comprising a solid phase comprising cellulose nanowhiskers embedded in a cellulose matrix. In one embodiment, the gel may comprise about 10 wt% to about 50 wt% cellulose nanowhiskers, measured as a percentage of the total cellulose content of the gel.
 In another aspect, the invention may comprise a method of forming a cellulose composite gel comprising the steps of:
a) forming an aqueous solvent comprising cellulose, sodium hydroxide, and urea; and dispersing cellulose nanowhiskers in the aqueous solvent to form a suspension;
b) heating the suspension to form a gel; and
c) immersing the gel in water to regenerate the gel.
In one embodiment, the aqueous solvent comprising sodium hydroxide, urea and water is cooled prior to addition of cellulose. The aqueous solvent may then be warmed to about room temperature prior to dispersion of the cellulose nanowhiskers. The suspension may be centrifuged and cooled prior to gel formation. The gel may be formed by heating the suspension may be heated at a temperature from about 30°C to about 40°C for about 30 minutes.  In one embodiment, the suspension comprises from about 20 wt% to about 50 wt% of cellulose nanowhiskers. In one embodiment, the suspension comprises about 20 wt% to about 35 wt% of cellulose nanowhiskers, and in another embodiment about 35 wt% to about 50 wt% of cellulose nanowhiskers.  In one embodiment, the gel may be formed or incubated in the presence of a therapeutic agent, which is thereby incorporated into the gel. The therapeutic agent may be a small molecule drug, such as a non-steroidal anti-inflammatory drug, or a large molecule drug, such as a protein.
 In another aspect, the invention may comprise a scaffold for tissue regeneration or wound repair, comprising a composite gel comprising cellulose nanowhiskers embedded in a cellulose matrix.
 In another aspect, the invention may comprise a method of regenerating tissue or repairing a wound comprising the steps of placing a composite gel as described herein, carrying a therapeutically effective amount of a therapeutic agent to provide a localized regenerating or repairing effect. In one embodiment, the tissue may comprise skin, muscle, bone or cartilage. The composite gel may be provided as a coating on, or filler in, a medical device such as a dressing, substrate or patch.
 Additional aspects and advantages of the present invention will be apparent in view of the detailed description, which follows. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. Brief Description of the Drawings
 The invention will now be described by way of an exemplary embodiment with reference to the accompanying simplified, diagrammatic, not-to-scale drawings:
 Figure 1 is a graph showing the angular frequency dependence of storage modulus (G ', ·) and loss modulus (G ", O) of cellulose solutions having different cellulose nanowhiskers contents at 25°C (the data are shifted along the vertical axis by 10 a with the given a value to avoid overlapping).
 Figures 2A-B are graphs showing (a) the temperature dependence of storage modulus (G ', ·) and loss modulus (G ", O) of cellulose solutions having different cellulose nanowhiskers contents with a heating rate of 2°C/min at a frequency of 1 Hz (the data are shifted along the vertical axis by 10° with the given a value to avoid overlapping), and (b) the gelation temperature and G ge i as a function of cellulose nanowhiskers content.
 Figure 3 is a graph showing the time dependence of storage modulus (G ', ·) and loss modulus (G ", O) of cellulose solutions having different cellulose nanowhiskers contents at 40°C and a frequency of 1 Hz (the data are shifted along the vertical axis by 10 a with the given a value to avoid overlapping).
 Figure 4 is a graph showing the angular frequency dependence of storage modulus ( ') of cellulose gels having different cellulose nanowhiskers contents before (solid symbols) and after (open symbols) regeneration in water at 25°C.
 Figures 5A-D show cellulose gels before (left) and after (right) regeneration in water at 25°C with different contents of cellulose nanowhiskers: 0 (a, b) and 50 wt% (c, d).
 Figure 6 is a graph showing the diffusion of sodium hydroxide from cellulose gels having different contents of cellulose nanowhiskers into the water regenerating bath at 25°C. The inset is a graph showing the dependence of sodium hydroxide diffusion coefficient on cellulose
nanowhiskers contents in a water bath at 25°C.
 Figures 7A-H are scanning electron micrographs of the cross-sections (left) and surfaces (right) of regenerated cellulose gels with different contents of cellulose nanowhiskers: 0 (a, b), 20 (c, d), 35 (e, f), and 50 wt% (g, h).  Figure 8 shows the FT-IR spectra of regenerated cellulose gels having different contents of cellulose nanowhiskers neat cellulose nanowhisker powder.
 Figure 9 is a graph showing the stress-strain curves of regenerated cellulose gels having different contents of cellulose nanowhiskers. The inset shows shear modulus with varying cellulose nanowhiskers contents.
 Figure 10 is a graph showing the swelling and re-swelling properties of regenerated cellulose gels with different contents of cellulose nanowhiskers.
 Figures 11 A-B are graphs showing release profiles of ibuprofen sodium (a) and bovine serum albumin (b) from drug-loaded cellulose gels with different contents of cellulose nanowhiskers in simulated body fluid at 37°C. The inset shows the diffusion coefficients with varying cellulose nanowhiskers contents.
Detailed Description of Preferred Embodiments
 The present invention relates to a composite gel comprising a matrix of cellulose and cellulose nanowhiskers dispersed within the matrix, methods for its production and its use as a scaffold in tissue regeneration or wound repair.
 When describing the present invention, all terms not defined herein have their common art-recognized meanings. To the extent that the following description is of a specific embodiment or a particular use of the invention, it is intended to be illustrative only, and not limiting of the claimed invention. The following description is intended to cover all alternatives, modifications and equivalents that are included in the spirit and scope of the invention. To facilitate understanding of the invention, the following definitions are provided.
 As used herein, the term "cellulose" means a linear homopolymer of glucose
(C 6 Hi 0 O 5 )„. In one embodiment, n ranges from about 500 to about 10,000. Cellulose from wood pulp has typical chain lengths between 300 and 1700 units; cotton and other plant fibers as well as bacterial celluloses have typical chain lengths ranging from 800 to 10,000 units. Cellulose comprises different polymorphs such as cellulose I, II, II or IV, which have differing crystalline structures.
 As used herein, the term "gel" means a solid three-dimensional cross-linked network that spans the volume of a liquid medium and ensnares it through surface tension effects. This internal network structure may result from physical or chemical bonds, as well as crystallites or other junctions that remain intact within the extending fluid. A gel comprises a composition that is of suitable viscosity for the intended purpose.
 Nanostructures include so-called one-dimensional nanoelements, essentially in one- dimensional form, that are of nanometer dimensions in their width or diameter (less than 100 nm), and that are commonly known as nanowhiskers, nanorods, nanowires, or nanotubes.
 Nanotechnology covers various fields, including that of nanoengineering, which may be regarded as the practice of engineering on the nanoscale. This may result in structures ranging in size from small devices of atomic dimensions, to much larger scale structures for example on the microscopic scale. Commonly, such structures include nanostructures. In certain contexts,
nanostructures are considered to be those having at least two dimensions not greater than about 100 nm, with some authors using the term to identify structures having at least two dimensions not greater than about 200 nm. As used herein, the term "nanowhisker" means a one dimensional nanoelement with a cross-dimension of nanometer size, including structures where at least two dimensions are not greater than about 200 nm.
 As used herein, the term "therapeutic agent" means any bioactive molecule capable of modifying or modulating the function of at least one given biological system. The term
"therapeutically-effective amount" means any amount of a formulation of a therapeutic agent which facilitates tissue regeneration or wound repair.
 As used herein, the terms "sustained release" or "sustainable basis" are used to define release of a therapeutic agent which continues over time, measured in hours or days.  As used herein, the term "substrate" means any surface, usually that of a medical device, which can be coated with a composite gel.  As used herein, the term "bioabsorbable" means capable of bioabsorption in period of time ranging from hours to years, depending on the particular application and "bioabsorption" means the disappearance or dispersal of materials from their initial application site in the body (human or mammalian) with or without degradation of the dispersed molecules.  As used herein, the term "biocompatible" means generating no significant undesirable host response for the intended utility. Most preferably, biocompatible materials are non-toxic for the intended utility. Thus, for human utility, biocompatible is most preferably non-toxic to humans or human tissues.  As used herein, the term "medical device" means any device, appliance, fixture, fibre, fabric or material intended for a medical, health care or personal hygiene utility, including, without limitation, orthopaedic pins, plates, implants, tracheal tubes, catheters, insulin pumps, wound closures, drains, shunts, dressings, connectors, prosthetic devices, pacemaker leads, needles, dental prostheses, ventilator tubes, surgical instruments, wound dressings, incontinent pads, sterile packaging, clothing, footwear, and personal hygiene products. The term "medical device" is intended to extend broadly to all such devices.
 The present invention relates to a cellulose composite gel comprising a solid phase comprising cellulose nanowhiskers embedded in a cellulose matrix. The composite gels are formed by a rapid thermally induced phase separation and regenerating process, without requiring any chemical modification or use of any organic solvent.
 In one embodiment, the invention comprises a composite gel comprising cellulose nanowhiskers dispersed in a cellulose matrix. In one embodiment, the gel comprises from about 5 wt% to about 60 wt% of cellulose nanowhiskers, as a percentage of the total cellulose content of the gel, or any percentage value or range therebetween. In one embodiment, the gel comprises from about 20 wt% to about 35 wt% of cellulose nanowhiskers. In one embodiment, the gel comprises from about 35 wt% to about 50 wt% of cellulose nanowhiskers. In one embodiment, the gel further comprises a therapeutic agent dissolved or carried in the liquid phase gel. In one embodiment, the therapeutic agent is a small molecule drug such as a non-steroidal anti-inflammatory drug, or it may be a large molecule drug such as a protein or biomolecule.  In one embodiment, the invention comprises a process for forming a composite gel comprising the steps of:
a) forming an aqueous solvent comprising cellulose, sodium hydroxide, and urea, and dispersing cellulose nanowhiskers in the aqueous solvent to form a suspension;
b) heating the suspension to form a gel; and
c) immersing the gel in water to regenerate the gel.
 In one embodiment, cellulose is used as the starting material to prepare the cellulose nanowhiskers and the cellulose-sodium hydroxide-urea aqueous solvent. Suitable sources of cellulose can include, without limitation, cotton short or cotton linter pulp. Preparation of cellulose
nanowhiskers is well known to those skilled in the art, and need not be further described herein. For example, cellulose nanowhiskers may be prepared by sulfuric acid hydrolysis from cellulose. In one embodiment, the cellulose nanowhiskers may be approximately 100 nm to 1 um in length, and about 5 nm to about 50 nm in width.  Cellulose nanowhiskers, obtained from a range of renewable bio-sources, have been successfully used as reinforcing fillers due to their large surface area and high mechanical
performances (Chen et al., 2009). However, cellulose nanowhiskers have a considerable tendency for aggregation via hydrogen bonds, therefore, in one embodiment, control of the "switching off and on" of the hydrogen bonding interactions during processing is preferred to ensure cellulose nanowhiskers can be uniformly dispersed in a solvent system at room temperature and then form strong hydrogen bonding interactions with cellulose matrix during gel formation.
 In the preparation of the aqueous solvent, sodium hydroxide, urea and water are cooled below room temperature prior to addition of cellulose, to facilitate the dissolution of the cellulose in the solvent. Once cellulose is added and dissolved, the aqueous solvent is warmed to about room temperature. The cellulose nanowhiskers are then dispersed in the cellulose-sodium hydroxide-urea aqueous solvent to form a suspension of the nanowhiskers. In one embodiment, the suspension may comprise from about 20 wt% to about 50 wt% of cellulose nanowhiskers. In one embodiment, the suspension comprises from about 20 wt% to about 35 wt% of cellulose nanowhiskers. In one embodiment, the suspension comprises from about 35 wt% to about 50 wt% of cellulose nanowhiskers.
 A gel may be created from the aqueous solvent through a thermally induced phase separation, utilizing a solvent with a low melting point which is relatively easy to sublime. The suspension may be centrifuged and cooled before being heated to form a physically cross-linked gel. In one embodiment, the suspension is heated at a temperature from about 30°C to about 40°C for about 30 minutes. The gel is regenerated through immersion in water to remove the solvent molecules, and to induce a further phase transition. In one embodiment, the gel is immersed in water for about 24 hours.
 In one embodiment, the gel is regenerated in an aqueous solution or suspension of a therapeutic agent. In another embodiment, the regenerated gel is further incubated in the presence of a therapeutic agent. In one embodiment, the incubation time is about 48 hours.
 In one embodiment, the composite gels are intended for medical applications, therefore, the use of organic solvents is preferably avoided. The process of the present invention is thus carried out, in one embodiment, without the use of any organic solvent.  Gelation behavior, regeneration kinetics, morphology and properties of the composite gel may be assessed using an advanced rheometer, potentiometric titration, scanning electron microscopy, Fourier-transform infrared spectroscopy, texture analyzer and swelling measurements.
 The interactions between the gel components (i.e., the cellulose matrix and the cellulose nanowhiskers) in the process of the present invention have been investigated. The cellulose nanowhiskers are well-dispersed in the cellulose matrix. Without restriction to a theory, it is believed that the cellulose and cellulose nanowhiskers combine with the solvent molecules at room temperature to form inclusion complexes by strong hydrogen bonding interactions which "switch off' the cellulose nanowhiskers. Figure 1 shows the G ' and G " as a function of angular frequency for the cellulose solution with different contents of cellulose nanowhiskers at 25° C. Urea hydrates may be self- assembled at the surface of the sodium hydroxide hydrogen-bonded cellulose to form an inclusion complex, leading to the dissolution of cellulose (Cai et al., 2005). It is thus likely that a competitive binding also forms between cellulose nanowhiskers and solvent molecules which then "switch off' the inter-particle hydrogen bonding interactions between cellulose nanowhiskers. For all the samples, G ' value was smaller than that of G " in the range of measured frequencies, exhibiting a viscous liquid-like behavior with G ' and G " scaling approximately with ω by G ', G " ~ ω (Cai et al. , 2006a). Both G ' and
G " values increased and the difference between these values became smaller when the content of cellulose nanowhiskers increased. Thus, strong interactions exist between cellulose nanowhiskers and solvent molecules to keep cellulose nanowhiskers "switched off," resulting in a good distribution of the cellulose nanowhiskers in the cellulose solution.
 When the temperature is raised, the inclusion complexes are destroyed and the hydrogen bonds between the cellulose molecules are "switched on" to facilitate the cross-linking of cellulose to form the composite gel. The crossover of G ' and G " curves was chosen as a qualitative indicator of the gel point, which showed only the transition current under external factors' influences (Sahiner et al, 2006). The gel point determined by this method is frequency dependent (Ruan et al, 2008). For consistency, a frequency of 1 Hz was fixed for all samples in the determination of the gel point and gelation time (Example 4). For all samples, G ' and G " curves were parallel when the temperature was below 30°C, indicating that the suspensions were stable. Above 30°C, G ' value increased dramatically and a crosspoint of G 'and G " curves appeared, suggesting the formation of an elastic gel network (Figure 2).  The strength of hydrogen bonding is dependent on temperature. Without restriction to a theory, it is believed that elevating the temperature leads to weakened hydrogen bond strength between the cellulose and solvent molecules, whereas the intra- and intermolecular hydrogen bonds of cellulose tend to increase as a result of its strong self-association tendency. The structures of inclusion complexes are thus destroyed, and physical entanglements and interchain interactions occur via self- association junctions on the cellulose backbone when the temperature was above 30°C, as an example of thermally induced phase separation. During the sol-gel transition, the hydrogen bonding interactions between the cellulose molecules are "switched on." With an increase in the content of cellulose nanowhiskers, the gelation temperature decreased from 37.2° to 33.8° C and the gel modulus (G ge i) raised from 9.4 to 20.0 Pa (Figure 2B), suggesting that cellulose nanowhiskers facilitate the cross- linking of cellulose molecules. This is further confirmed by results which shows the time dependence of G 'and G " curves of cellulose solutions with different contents of cellulose nanowhiskers at 40° C (Figure 3). The gelation of the suspensions took place at 40° C within 150 s. With the addition of cellulose nanowhiskers, the gelation time decreased from 143.9 to 124.4 s. It is assumed that a more jammed cellulose suspension is formed when the cellulose nanowhisker content is high, so that the distances among cellulose molecules are greatly shortened. When the temperature is raised to 40° C to destroy the inclusion complexes, the hydrogen-bonding interactions among cellulose chains are "switched on" more easily and rapidly. Moreover, the rod-like cellulose nanowhiskers may act as reinforcement to mediate between the cellulose chains by developing cellulose-cellulose nanowhisker hydrogen bonds at the "switching on" status to promote the gelation process and support the gel network.
 During gel regeneration, the aqueous solvent (sodium hydroxide-urea-water) is replaced by water which is miscible with the aqueous sodium hydroxide-urea solution, to trigger a phase separation. Figure 4 shows the mechanical property of cellulose gels before and after regeneration. Before regeneration, cellulose molecules and cellulose nanowhiskers are bound by hydrogen bonds. The G ' curves of the samples presented a plateau-like behavior at lower frequencies, and their heights increased and the widths expanded with the increase in nanowhisker content, indicating that the hydrogen bonded network, containing more nanowhiskers as the crosslinking points, was stronger and more elastic. The G ' curve of CC50 was flat and much higher than other curves, the result of the extremely jammed network caused by the high nanowhisker content. When the gels are immersed in the water bath, another phase separation takes place, resulting in a further physically cross-linked cellulose molecular chain entanglement and the formation of new cellulose crystalline regions. The plateaus of G ' curves raised approximately three orders of magnitude after regeneration. A reinforcing effect may still be observed in the composite gels, suggesting the strong reinforcement of cellulose nanowhiskers even in a tough matrix.
 The cellulose nanowhiskers provide a good support to the cellulose matrix to maintain homogeneous shrinkage. Figure 5 shows samples before and after regeneration in water at 25°C.
Before the regeneration, CC0 exhibited a weak character with an unstable shape, whereas CC50 acted like elastic foam with well-formed dimensions. The gel mechanical property was significantly improved by addition of nanowhiskers. An irregular shrinkage of CC0 occurred during gel regeneration (Figure 5 b). That was because the shrinking rate of every part on the gel was different, so as to distort the regenerated gel. However, CC50 exhibited a similar shape before and after regeneration. CC20 and CC35 also exhibited well-formed dimensions and the extent of shrinkage decreased when the nanowhisker content increased. Abundant hydrogen bonding interactions were "switched on" between cellulose nanowhiskers and cellulose molecules, which formed a strong, elastic network to support and diffuse the stress faster and uniformly, leading to the homogeneous shrinkage. It is thus easy to control the shape of the regenerated products and a uniform inner porous structure can be expected in the composite gel.  Further, the cellulose nanowhiskers may promote the diffusion of solvent and non- solvent molecules. The kinetics of cellulose regeneration is controlled by the diffusion of sodium hydroxide and urea from the cellulose gels into the regeneration bath and of the non-solvent from the bath into the cellulose gels. The kinetics of cellulose regeneration in the presence of the different contents of cellulose nanowhiskers were investigated by measuring the evolution of sodium hydroxide concentration in the water bath. Figure 6 shows the diffusion of sodium hydroxide as a function of time. Fickian diffusion mechanism was employed to fit the experimental data. It is widely applied in drug release from a polymeric matrix (Singh et al. , 2007), the formation of membranes due to phase separation, the kinetics of cellulose regeneration from cellulose-N-methylmorpholine-N-oxide-water (Biganska et al., 2005) and cellulose-sodium hydroxide- water solutions (Sescousse et al, 2009;
Kokubo et al. , 2006). The Fickian model is calculated from the following equations:
(a) Early-time approximation (0 < M,/M ∞ < 0.5):
(b) Half-time approximation (M t /M ∞ = 0.5):
D = 0.049/(t// 2 ), /2 (2) (c) Late-time approximation (0.5 < M t /M ∞ < 1): where (M t IM m ) is the fractional release, M t and M ∞ are the amounts released at time t and equilibrium, respectively, D is the diffusion coefficient and / is half of the thickness of the sample. The diffusion profiles of sodium hydroxide were well fitted with early-, half-, and late-time approaches (R 2 = 0.99), indicating the validity of the Fickian approach for the composite gels. The diffusion coefficient was calculated by the half-time approximation and plotted in the insert of Figure 6. The diffusion behavior of the sodium hydroxide from the gel matrix was mainly controlled by "porous membrane" instead of the "hydrogel-obstruction" because a relatively lower diffusion coefficient was observed (Kokubo et al., 2006). CC0 displayed a lowest diffusion coefficient (1.60 x 10 "4 mm 2 /s), while the diffusion coefficient increased to the maximum (2.58 χ 10 "4 mm 2 /s) in CC20 and then decreased with the further addition of cellulose nanowhiskers.
 Besides the "porous membrane," the inner structure of the composite gels may also contribute to the regenerating process, and a stable and well-supported architecture was propitious to the diffusion of sodium hydroxide and water molecules, leading to the high regenerating rates of CC20 and CC35. With the increase in content of cellulose nanowhiskers, the more jammed hydrogen bonded networks were formed which lower the diffusion rate of sodium hydroxide, resulting in an obviously decreased diffusion coefficient of CC50 (1.93 χ 10 "4 mm 2 /s).  The composite gel formed from the process of the present invention is porous, while the surface is denser (Example 5). It appears that the cellulose nanowhiskers improve the dimensional stability and mechanical properties of the regenerated composite gel. Figure 7 shows SEM images of the cross-sections and surfaces of regenerated cellulose gels with different contents of cellulose nanowhiskers. More homogeneous porous architectures were observed in CC20 and CC35 than that of CC0. The shrinkage during the regeneration was irregular in CC0 and was controlled by the support of cellulose nanowhiskers in CC20 and CC35. It was difficult to distinguish cellulose nanowhiskers or their aggregates on the cross-section of CC20, indicating that cellulose nanowhiskers were well dispersed and embedded in the regenerated cellulose matrix. When the content of cellulose
nanowhiskers was 35 wt%, pores with tiny branches appeared (see insert of Figure 7E). With increased cellulose nanowhisker content, the regenerated cellulose matrix could not cover all the cellulose nanowhiskers and some of them were exposed after shrinkage. It also demonstrates the uniformly dispersion of cellulose nanowhiskers was caused by a "switching off process at the suspension status, and after regeneration, cellulose nanowhiskers were still well distributed in the network. However, fewer pores existed on the cross-section of CC50 due to a more jammed hydrogen bonded network formed in CC50 and the distance between cellulose nanowhiskers was much closer than those in other suspensions, as shown in rheological tests. Thus, cellulose nanowhiskers combined together to come into the phase continuity and blocked the pores during the regeneration. Similar dense surfaces, which demonstrated the same appearance as porous membranes, were observed in all samples. Without being bound by a theory, it is possible that a high diffusion rate of the solvent and non-solvent molecules existed on the surfaces of the gels, leading to a strong shrinkage which was beyond the support of cellulose nanowhiskers. The observed surface morphology concurs with the results of a regeneration kinetic test. The composite gels thus demonstrate unique structures, featuring denser membrane-like surfaces and various porous inner architectures reinforced by cellulose nanowhiskers.
 Infrared spectrometry has been used to study hydrogen bonding behavior and cellulose crystalline structure ( ondo et al , 2008; ataoka et al, 1998). Figure 8 shows the FT-IR spectra of cellulose gels and neat cellulose nanowhisker powder. For the sample of cellulose nanowhisker, the absorbance of the bands at 3344 and 710 cm "1 revealed that it was cellulose I p crystalline (Sugiyama et al , 1991 ; Oh et al , 2005a), which is thermo-dynamically stable (Akerholm et al, 2004) and prevails in cotton and tunicate cellulose (Azizi Samir et al, 2005). The absorbance of the band at 1430 cm "1 also corresponds to a crystalline absorption and is closely related to the portion of cellulose I structure (Oh et al , 2005b). When cellulose nanowhisker content was 20 wt%, the absorbance of the bands at 1430 and 710 cm "1 was very weak, indicating that cellulose nanowhiskers (cellulose Ι β ) were dispersed and embedded in the regenerated cellulose matrix (cellulose II) by "switching off and on" the inter-particle hydrogen bonding interactions, which was observed by SEM. With increased cellulose nanowhisker content, cellulose nanowhiskers were exposed and gradually formed the continued phase, resulting in the increased intensity of the peaks at 1430 and 710 cm "1' The addition of cellulose nanowhiskers might disturb the original interactions existing in neat cellulose gel and affect the formation of regenerated cellulose crystal. For the CC0 sample, the hydrogen bonded -OH groups stretching vibration exhibited a strong absorption peak centered at 3460 cm "1' This absorption peak gradually shifted to lower wave numbers at 3417 cm "1 and its intensity increased with the higher cellulose nanowhisker content, confirming that a stronger and denser hydrogen bonded network formed in the composite gels when cellulose nanowhiskers acted as the cross-linking point and scaffold.
 In one embodiment, the composite gel may be used as a scaffold for tissue regeneration or wound repair. As used herein, the term "tissue" means a group or layer of similarly specialized cells that together perform certain special functions. As used herein, the term "tissue regeneration" means the engineering or creation of tissue. As used herein, the term "scaffold" means a structure capable of supporting three-dimensional tissue growth by allowing cell attachment and migration, delivering and retaining cells and biochemical factors, enabling diffusion of vital cell nutrients and expressed products, and/or exerting certain mechanical and biological influences to modify the behaviour of the cell phase.
 The unique structure of the composite gel confers a rubber-like mechanical property, which makes it suitable for use as a tissue scaffold such as, for example, cartilage tissue. The mechanical performance of the regenerated cellulose gels was evaluated under compression, and the stress-strain curves are shown in Figure 9. The neo-Hookean constitutive relationship for rubbers was utilized to analyze the data. In this model, an expression for stress (σ) is derived as the following equation (Sanabria-DeLong et al, 2008):
σ = 2C 1
(ε + I) 2 (4) where is the strain, and the single parameter C \ is defined as half of the shear modulus, G (C\ = GI2). The fit was in agreement with the stress-strain curves and predicted the observed nonlinear behavior well (R 2 = 0.99), suggesting that the regenerated gels were a rubbery material. By using the neo- Hookean fit, the shear modulus of the regenerated cellulose gels was calculated and plotted in the insert of Figure 9. With increased cellulose nanowhisker contents, the shear modulus of neat cellulose gel increased from 81 kPa to 160 kPa, while a much strengthened stress was also observed, indicating a reinforcing effect. There was a linear dependence of shear modulus on the cellulose nanowhisker concentration. This effect could be explained based upon the composite gel structure. As described, cellulose nanowhiskers were dispersed and acted as the cross-linking points in the gel network to form the jammed hydrogen bonded architecture. If it is assumed that cellulose nanowhiskers were well- dispersed and all of them contributed to the network, then the cross-links would be linearly increased. Because the modulus was directly proportional to the cross-link density, the linear relationship between the modulus and the cellulose nanowhisker content further confirms that cellulose nanowhiskers were satisfactorily "switched off and well dispersed in the regenerated cellulose matrix, and were "switched on" during gel thermal treatment and regeneration, leading to the homogeneous distribution of the cellulose nanowhiskers in the gel matrix to render a better reinforcement (Sanabria-DeLong et al. , 2008). The composite gel of the present invention exhibits a similar modulus compared to those of PLA-PEO-PLA hydrogels (Sanabria-DeLong et al. , 2008) and PLA-fibrin gels (Zhao et al. , 2009) which have been proposed as cartilage tissue engineering materials.
 In one embodiment, the invention comprises a method of regenerating tissue or repairing a wound comprising contacting a problem area or wound with the composite gel carrying a therapeutically effective amount of a therapeutic agent to provide a localized regenerating or repairing effect. In one embodiment, the composite gel may release the therapeutic agent on a sustainable basis and at a concentration sufficient to provide a regenerating or repairing effect.
 The composite gel exhibits loading and controlled-releasing abilities to deliver therapeutic agents. Figure 10 shows the swelling and re-swelling properties of the regenerated gels with different contents of cellulose nanowhiskers (Example 7). The equilibrium swelling ratio (ESR) was calculated to assess gel swelling ability. All samples had relatively strong water-holding capacity. ESR values were impacted by the content of cellulose nanowhiskers in the gel matrices. As the cellulose nanowhisker content increased from 0 to 50 wt%, ESR values of the composite gels gradually decreased from 9.88 to 6.50. Without being bound to a theory, this result may be due to the increased cross-linking density which restricted the swelling of regenerated cellulose matrix. The gels were then freeze-dried for testing re-swelling. Much lower water content was observed in the re-swelled gels. When immersed in a water bath, dried gels swelled to different extents depending on their cellulose nanowhisker contents. The composite gels containing more cellulose nanowhiskers exhibited higher re-swelling ratios. A stiffer network was formed at a high content of cellulose nanowhiskers, which could prevent further cross-linking of the cellulose chains during the drying processing and were propitious to the water uptake. Considering the different water-holding capacities, the composite gels were further tested as drug carriers.
 The controlled release properties of the composite gel were determined in simulated physiological conditions using ibuprofen sodium (IBU-Na, representing a non-steroidal anti- inflammatory drug having a small molecular size) and bovine serum albumin (BSA, representing a protein drug having a larger molecule size compared to IBU-Na) as test drugs (Example 8). Figures 11 A-B show the release profiles of IBU-Na and BSA in simulated body fluid at 37°C. The amounts of the drugs released at equilibrium, M ∞ , were tested after incubating for 48 hours. Both IBU-Na and BSA molecules could travel through the pores and be adsorbed in the gels to achieve a considerable drug loading content (89.09 ± 4.65 mg/g for IBU-Na and 12.50 ± 1.31 mg/g for BSA). The release data were analyzed according to zero-order and first-order kinetics as well as the Fickian model using linear regression analysis. The results revealed that an approximate zero-order profile (M t IM ∞ versus f) exhibited at the early time of the drug release process (within 60 min), and then the release data occurred through the Fickian diffusion mechanism (M,/M ∞ versus t m , R 2 = 0.99).
 Without being bound by a theory, it is believed the release process of the loaded drugs involved two kinds of diffusion. First, drug molecules diffused from the matrix to the surface layer and through the surface layer to simulated body fluid. At the initial stage of release, the thickness of the drug depletion zone was very small in magnitude and the rate-controlling step resided in the membrane-like dense surfaces, thus an approximate zero-order drug release profile exhibited. Next, as the duration of drug release was prolonged, the receding interface of the drug depletion zone/drug dispersion zone progressed to the extent that the diffusion process through the matrix became the
1/2 predominant step in determining the release rate, resulting in the relationship of M t IM ∞ versus t (Chien, 1992).
 The diffusion coefficients were calculated and plotted in the inserts of Figure 11. The IBU-Na loaded cellulose gels with different contents of cellulose nanowhiskers exhibited similar release behaviors, and approximately 60% of the loaded drug was released through a near zero-order profile. It implied that the membrane-like dense surface controlled diffusion was the main step in the release of small drug molecules. IBU-Na could diffuse freely in all the cellulose matrices with different contents of cellulose nanowhiskers, so the tortuosity of the matrix did not affect the release, resulting in the similar profiles. BSA has a larger molecular dimension. During the same period, the percent cumulative release and the diffusion coefficients of BSA were much lower than those of IBU- Na, suggesting a better controlling ability to the bigger molecules. The release rate of BSA-loaded CC0 was the fastest and about 36% of the loaded drug was released in the first 60 min, while BSA loaded CC20, CC35 and CC50 showed the similar lower release behaviors at the early stage. Some irregular big pores existed in CC0, as observed by SEM, which enlarged the drug depletion zone and led to a faster "membrane" controlled diffusion rate. As the duration of BSA release was prolonged, the diffusion of BSA was controlled by the matrix of the gels. The diffusion coefficient of the composite gels decreased dramatically from 0.42 χ 10 "4 to 0.21 χ 10 "4 mm 2 /s with the cellulose nanowhisker content increased from 0 to 20 wt%, and then raised gradually to 0.30 χ 10 "4 mm 2 /s when the cellulose nanowhisker content was 50 wt%, suggesting the different matrix controlled diffusions of BSA. As discussed above, CC20 and CC35 exhibited homogeneous porous structures, so their tortuosity of the matrix was much higher than that of CC0, and the diffusion of BSA in CC20 and CC35 was slower. For CC50, cellulose nanowhiskers combined together and blocked some pores in the gel; thus, it might be difficult for BSA to penetrate into the inside of the composite gel during the drug loading process, leading to a higher BSA loading at the matrix surface and consequently a slightly increased diffusion coefficient. Overall, the results show that the composite gel may be used as a membrane-matrix hybrid delivery system for the controlled release of macromolecular drugs.  Medical devices may be formed from, incorporate, carry or be coated with the composite gel of the present invention. The medical device may be bioabsorbable. The medical device may contact a problem area or wound (for example, a body tissue such as skin, muscle, cartilage or bone requiring treatment) for any period of time such that tissue regeneration or wound repair is possible. The tissue regeneration or wound repair effect of the composite gel is achieved when the medical device formed from, incorporating, carrying or coated with the composite gel is brought into contact with the problem area or wound, thus releasing the therapeutic agent. The amount of the therapeutic agent which is needed to produce a tissue regeneration or wound repair effect will vary with the type and severity of the wound, the frequency and route of administration, the type and concentration of the therapeutic agent in the composite gel, and the age, body weight and response of the patient. Appropriate amounts in any given instance will be readily apparent to those skilled in the art or capable of determination by routine experimentation.
 In one embodiment, the composite gel carrying the therapeutic agent may be provided as a coating on, or filler in a medical device. In one embodiment, the medical device is selected from a dressing, substrate or patch. The coating is formed as a thin film on at least a part of the surface of the medical device. The film has a thickness no greater than that needed to provide release of the therapeutic agent on a sustainable basis over a suitable period of time.
 Exemplary embodiments of the present invention are described in the following Examples, which are set forth to aid in the understanding of the invention, and should not be construed to limit in any way the scope of the invention as defined in the claims which follow thereafter.
Example 1 - Materials
 Cellulose (cotton linter pulp) was provided by Hubei Chemical Fiber Group Ltd.
(Hubei, China). Its viscosity-average molecular weight ( η ) was determined by using an Ubbelohde viscometer in LiOH/urea aqueous solution at 25 ± 0.05°C and calculated according to the Mark- Houwink equation (Cai et al , 2006b) to be 3.0 10 5 . Ibuprofen sodium (IBU-Na) and bovine serum albumin (BSA, Fraction V) were purchased from Sigma- Aldrich (MO, USA). All other chemical reagents were purchased from Fisher Scientific (Ontario, Canada).
Example 2 - Preparation of cellulose nanowhiskers
 Cellulose (20 g) was dispersed in 175 mL of a 30 vol. % sulfuric acid, and the mixture was added to a three-necked flask equipped with a mechanical stirrer and a thermometer. The flask was placed into a water bath at 60°C and stirred vigorously for 6 hours. The suspension was then diluted with distilled water, and centrifuged at 8000 rpm (Avanti™ J-E centrifuge, Beckman Coulter, USA) for 15 minutes. The process was repeated three times to remove the excess sulfuric acid. The resulting suspension was dialyzed for 2 hours in running water and then overnight in distilled water, until the pH reached 4. Finally, the dispersion was treated with an ultrasonicator and freeze-dried to obtain cellulose nanowhisker powder (CN). The average length (Z) and width (D) of CNs observed by atomic force microscopy (AFM) were estimated to be 300 and 21 nm, respectively (Wang et al, 2010).
Example 3 - Preparation of composite gels
 A 100 g mixture of sodium hydroxide, urea, and distilled water (7: 12:81 by weight) was precooled to -12.6°C, and 4 g of cellulose was added immediately with vigorous stirring for 5 minutes to obtain a transparent solution. After warming to room temperature, a desired amount of CN was added to the solution and stirred for 30 minutes. The suspension was centrifuged at 3000 rpm and 10°C for 5 minutes to remove air bubbles, and then injected into a plastic tube. The sealed tubes were then heated in a water bath at 40°C for 30 minutes to obtain physically crosslinked gels. Then the gels were removed from the tubes and regenerated in running water for 24 hours. These all-cellulose composites were coded as CC0, CC20, CC35 and CC50, corresponding to a CN content (based on the total solid content) of 0, 20, 35 and 50 wt%, respectively. Example 4 - Kinetics of composite gel formation
 To understand the variation of the structures of all-cellulose composites during the thermal-induced phase separation process, the dynamic rheology experiment was carried out on an ARES-2000™ rheometer (TA Instruments, U.S.A.). Parallel plate geometry with a gap of 1 mm was used to measure dynamic viscoelastic parameters such as the shear storage modulus (G ') and loss modulus (G ") as functions of angular frequency (&>), temperature (7), or time (t). The values of the strain amplitude were monitored to ensure that all measurements were set as 10%, which is within a linear viscoelastic regime. For each measurement, a fresh sample was used without preshearing or oscillating. To prevent dehydration during rheological measurements, a thin layer of low-viscosity paraffin oil was spread on the exposed surface of the measured suspension. For the frequency and time sweep measurements, time t = 0 min was defined when the temperature reached the desired value. The sweep of the frequency was from 0.1 to 100 rad/s. The dynamic temperature sweep measurements were conducted from 20 to 50°C at an angular frequency of 1 Hz and with heating rates of 2°C /min. The gelation behavior was studied at 40°C as a function of time at a constant frequency of 1 Hz.
 The diffusion of sodium hydroxide, urea and water took place when all-cellulose gels were immersed in the regenerating bath. To investigate the regeneration process, the evolution of sodium hydroxide concentration in the water bath as a function of time was measured using titration with acetic acid in the presence of an indicator (Gavillon et al. , 2007). The proportion between sample/bath weights was 1/400, and magnetic stirrer with a low stirring rate (300 rpm) was used for bath homogenization. The amount of sodium hydroxide released from the sample in time was calculated knowing the initial sample and bath weights. Example 5 - Structure of the composite gel
 The morphology observation of the regenerated gels was carried out with a Hitachi X- 650™ scanning electron microscope (SEM, Hitachi, Japan). The samples were frozen in liquid nitrogen and snapped immediately, and freeze-dried before SEM observation. The cross-sections and surfaces of the gels were sputtered with gold, observed and photographed. The cellulose crystalline structure and interaction in the regenerated gels were studied with a Perkin Elmer Spectrum™ One
FTIR spectrophotometer (Wellesley, MA, USA) in the region of 400-4000 cm "1 . The freeze-dried gels and CN powder were analyzed in KBr discs.
Example 6 - Mechanical properties of the composite gel
 The mechanical properties of the regenerated gels were analyzed by a texture analyzer (Texture Technologies Corp., New York, USA). The gels with a cylindrical shape, i.e. -10 mm in diameter and ~7 mm in height, were compressed at room temperature in air at a rate of 1 mm/min to evaluate their mechanical property. Raw data (force vs displacement) were converted to engineering stress and strain by the use of the initial dimensions of the gels.
Example 7 - Swelling measurements for the composite gel
 The swelling ratio of the regenerated gels with different CN contents was analyzed with a gravimetric method in the distilled water at 25 °C. After the surfaces of the gels had been wiped with filter papers to remove excess water, the weights of the hydrogels were recorded. The equilibrium swelling ratio (ESR) was calculated as:
ESR = W Wi (5) where W s is the weight of the regenerated gel at 25°C, and W d is the weight of the gel at dry state. To clarify the reswelling, the freeze-dried hydrogel samples were again immersed in distilled water to rehydrate at 25°C for 24 hours. The results were expressed as water reuptake WR), and can be calculated by:
WR = (W r - W d ) / (W s - Wi) x 100 (6) where W T is the weight of the reswelling gel, and other symbols are the same as defined above. Example 8 - Release property of the composite gel
 The typical drug loading and in vitro drug release experiment were performed as follows: IBU-Na and BSA were selected as model drugs which represented small and large molecules to investigate the gel release properties. Simulated body fluid (SBF) was employed as the media and prepared by dissolving the following reagents in 1 L of ion-exchanged and distilled water : NaCl = 8.035 g, NaHC0 3 = 0.355 g, KC1 = 0.225 g, Κ 2 ΗΡ0 4 ·3Η 2 0 = 0.231 g, MgCl 2 -6H 2 0 = 0.311 g, 1.0 M- HC1 = 39 ml, CaCl 2 = 0.292 g, Na 2 S0 4 = 0.072 g, Tris = 6.118 g. Cylindrically swelled cellulose gels (-0.5 g) were immersed entirely in the drug solutions (100 mg mL "1 IBU-Na and 20 mg mL "1 BSA SBF solutions) and incubated in sealed vessels at 0°C for 24 hours. The drug loading content (L was calculated by the following equation:
LC = W id / W s (7) where W \d is the weight of the loaded drugs in the regenerated gels.
 Drug loaded gels were then separated, wiped with filter papers to remove excess solution, and kept in 200 mL of SBF at 37°C with shaking at a constant rate. The release medium (1 mL) solution was taken out for analysis at given time intervals and replaced with the same volume of fresh preheated SBF (37°C). The extracted medium solution was analyzed using a Jasco V-530 UV- VIS Spectrophotometer (Jasco Inc., USA) at a wavelength of 263 nm for IBU-Na and 280 nm for BSA. The release data were fitted to the following equations using regression analysis:
 Zero-order equation dM t / dt = k, (8)
where k is the constant, t is time, and M t is the amount of drug released at time t.  First-order equation d t / dt = k(M 0 - t ), (9)
where k is the constant, / is time, 0 and M t are the amounts of drug released at time 0 and t.
 Fickian model M, / M ∞ = kt 0 5 (10)
where M,/M ∞ is the fraction of drug released after time t relative to the amount of drug released at infinite time.
Example 9 - Statistical analyses
 All experiments were performed at least in triplicate. The error bars on the graphs represent standard errors obtained from the statistical model.
 The following references are incorporated herein by reference (where permitted) as if reproduced in their entirety. All references are indicative of the level of skill of those skilled in the art to which this invention pertains.
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