Biomaterials

Details Biomaterials Biomaterials

2001-08-14

2003-01-07

Foelak, Morton (Department: 1711)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Cellular products or processes of preparing a cellular...

C521S145000

Reexamination Certificate

active

06503958

ABSTRACT:

The present invention relates to porous polymers incorporating dihydroperfluoroalkyl acrylates and methacrylates and the like and their production. The invention also relates to the use of polymers derived from dihydroperfluoroalkyl acrylates and methacrylates and like compounds, in both porous and non-porous forms, as substrates for the attachment and growth of mammalian cells and tissue. The invention also relates to the use of polymers derived from dihydroperfluoroalkyl acrylates and methacrylates as components of medical devices and prostheses, including implanted devices. In many applications it has been found advantageous for polymers to be porous. The degree of porosity required depends on the application. For example, membrane filtration depends on the use of microporous polymers to effect separations of various materials; macroporous sheets of chemically resistant polymers find extensive use as dividers in cells for electrolysis or electricity storage. Furthermore, porosity is often advantageous in synthetic polymers used in medical devices and prostheses implanted into tissue. This is the case where vascularisation of the implant is preferred or required, in which case the porosity enhances ingrowth of the blood vessels. It is also the case for some implants into non-vascular tissue, such as the case of a corneal onlay. U.S. Pat. No. 5,713,957 teaches that, in epikeratoprostheses, transmission of nutrients is an important factor for the maintenance of a healthy epithelium. Many other applications of polymers in medicine or surgery also require porosity or are optimal when the substrate is porous. These include artificial skins, drug delivery reservoirs, and soft tissue implants.
It is often useful for the porous polymer to be transparent and resistant to fouling and deposition. This is the case for some industrial membrane applications where the transparency allows inspection of the integrity of the membrane. Transparency of a synthetic polymer or porous polymer can also be an advantage for certain biomaterial applications, including for example the case of wound dressings where the transparency of the material allows for the progress of wound healing to be monitored without the dressing needing to be removed, or for some cases of implanted materials, an example being that of ocular implants.
Much of the prior art concerning cell and tissue colonisation of synthetic biomaterials teaches that adhesion of cells to hydrophobic polymeric substrates requires the surface chemistry of the synthetic polymer to be specifically modified to facilitate the adhesion and growth of cells. Stimulation of cellular attachment via adsorption or covalent attachment of one or more cell-adhesive molecules (such as fibronectin, vitronectin or collagen) or fragments thereof has also been used.
WO96/31548 discloses a class of materials based on perfluoroalkylpolyether macro-monomers, which in both their porous and non-porous forms can act as cell growth substrates and are suitable for use as biomaterials, particularly in ocular applications. WO96/31548 also discloses perfluoroalkylpolyether-containing compositions copolymerised with comonomers including minor amounts of dihydroperfluorooctyl acrylate. Although perfluoropolyethers as a general class of materials have many advantages, they suffer limitations in terms of cost and difficulty of purification. It would be useful if more readily available and simple monomers could be found with advantageous properties in terms of cell growth and/or being fabricated with porosity whilst maintaining clarity. We have now found that polymers and copolymers that are devoid of perfluoroalkylpolyether units but are based on free radically polymerisable monomers containing residues derived from fluorine containing alcohols and amines possess these properties and are particularly suitable as biomaterials, artificial cornea substrates and for use in other cell growth and membrane applications.
According to one aspect of the present invention there is provided a porous polymer that is obtained by polymerising a polymerisable component comprising
(i) a free radically polymerisable unsaturated monomer of formula
Q—X—A  (1),
wherein Q is a radical of formula
Q
1
is a radical of formula
(alk) is linear or branched C
2
-C
12
-alkylene,
(alk′) is linear or branched C
1
-C
12
-alkylene,
R is an olefinically unsaturated copolymerisable radical having from 2 to 24 carbon atoms which may be further substituted,
each of s and t is independently of the other the number 0 or 1,
X is a group —O—, —S— or —NR
1
— and R
1
is hydrogen, C
1
-C
4
-alkyl or a radical A, and
A is a radical of formula
—[(CH
2
)
a
—(Y)
z
—(CHF)
b
—(CF
2
)
c
]—R
2
  (4),
wherein R
2
is hydrogen or fluorine, Y is a group —N(R
3
)SO
2
—, —OSO
2
—, —OC(O)— or —N(R
3
)C(O)—, R
3
is hydrogen or C
1
-C
4
-alkyl, z is an integer of 0 or 1, a is an integer from 1 to 15, b is an integer from 0 to 6, and c is an integer from 1 to 20;
or A is partly or wholly fluorinated C
4
-C
8
-cycloalkyl,
and optionally
(ii) a comonomer and/or
(iii) a crosslinker,
wherein the porous polymer has a water content when fully swollen in water which is higher than that of the same polymer if polymerised under conventional conditions.
Suitable substituents on the olefinic C
2
-C
24
radical R are, for example, C
1
-C
4
alkoxy, halogen, phenyl or carboxy. R is, for example, a radical of formula
wherein l is the number 0 or 1, R
4
is hydrogen, C
1
-C
4
-alkyl or halogen, each of R
5
and R
6
independently of the other is hydrogen, C
1
-C
4
-alkyl, phenyl, carboxy or halogen, and R
7
is linear or branched C
1
-C
12
-alkylene or unsubstituted or C
1
-C
4
-alkyl- or C
1
-C
4
-alkoxy-substituted phenylene or C
7
-C
12
-aralkylene.
When R
7
is a phenylene radical, it is, for example, unsubstituted or methyl- or methoxy-substituted 1,2-, 1,3- or 1,4-phenylene. Preferably, R
7
as a phenylene radical is 1,3- or 1,4-phenylene.
When R
7
is an aralkylene radical, it is, for example, unsubstituted or methyl- or methoxy-substituted benzylene. Preferably, R
7
as an aralkylene radical is the 1,3- or 1,4-phenylenemethylene radical.
R
7
is preferably unsubstituted or methyl- or methoxy-substituted phenylene or phenylene-methylene or C
1
-C
12
alkylene, more preferably 1,3- or 1,4-phenylene or C
1
-C
6
alkylene, especially C
1
-C
2
alkylene and most preferably methylene.
l is the number 1 or, preferably, the number 0. R
4
is preferably hydrogen, methyl or chlorine and most preferably hydrogen or methyl.
Each of R
5
and R
6
independently of the other is preferably hydrogen, carboxy, chlorine, methyl or phenyl. In a preferred embodiment of the invention, R
5
is hydrogen, chlorine, methyl or phenyl and R
6
is hydrogen or carboxy. Most preferably, R
5
and R
6
are each hydrogen.
Examples of suitable radicals R are vinyl, 1-methylvinyl, 2-propenyl, allyl, 2-butenyl, o-, m- or p-vinylphenyl, styryl, 2-carboxyvinyl, 2-chloro-2-carboxyvinyl, 1,2-dichloro-2-carboxyvinyl, 1,2-dimethyl-2-carboxyvinyl and 2-methyl-2-carboxyvinyl.
Especially preferred radicals R correspond to formula (5) wherein l is 0, R
4
is hydrogen or methyl, R
5
is hydrogen, methyl, chlorine or phenyl, in particular hydrogen, and R
6
is carboxy or particularly hydrogen.
Other especially preferred radicals R correspond to the above formula (5) wherein l is 1, R
7
is 1,3- or 1,4-phenylene or C
1
-C
6
-alkylene, especially C
1
-C
2
-alkylene, R
4
is hydrogen or methyl and R
5
and R
6
are each hydrogen.
(alk) is preferably C
2
-C
6
-alkylene, more preferably C
2
-C
4
-alkylene and in particular ethylene. (alk′) is preferably C
1
-C
4
-alkylene, especially methylene or 1,1-dimethylmethylene.
One group of suitable radicals Q corresponds to the above formula (2) wherein s is 0 and Q
1
is a radical of the above formula (3a) wherein t is 0 and for R the above given meanings and preferences apply. A second group of suitable radicals Q corresponds to the above formula (2) wherein s is 1 and Q
1
is a radical of the above formula (3

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