1. HYDROPHILIC
POLYMERS FOR PREVENTION OF SURGICAL ADHESIONS
2. SURFACE
MODIFIED VASCULAR GRAFTS AND STENTS
3. SURFACE
MODIFIED CATHETERS
4. SURFACE
PROPERTIES AND ACCELERATED EVALUATION OF IMPLANTS
5. HYDROGRAFTTM
HYDROPHILIC POLYMER SURFACE MODIFICATION
6. BIOCOMPATIBILITY
OF IMPLANTS AND DEVICES
7. OPHTHALMIC POLYMERS WITH
IMPROVED MECHANICAL AND OPTICAL PROPERTIES
8. LOW-COST/HIGH
PERFORMANCE OPHTHALMIC VISCOELASTICS
9. SURFACE
MODIFICATION OF OCULAR IMPLANTS
10. SILICONE
BREAST IMPLANT RESEARCH
11.
LOCALIZED AND CONTROLLED DRUG DELIVERY USING MICROSPHERE CARRIERS
AND AFFINITY BINDING LIGANDS
12.
MICROSPHERES FOR CELL SEPARATIONS
13. TISSUE-PROTECTIVE SOLUTIONS
FOR HARVESTING CELLS AND BIOPROSTHESES
14. WOUND HEALING, CELL-SURFACE
INTERACTIONS, AND TISSUE REGENERATION
15. NERVE TISSUE REGENERATION AND REPAIR
REPRESENTATIVE
RECENT PAPERS AND PUBLICATIONS
1. HYDROPHILIC POLYMERS FOR PREVENTION OF SURGICAL ADHESIONS
Normal surgery involves
frequent manipulative contacts between tissue surfaces and various metal,
glass or plastic instrument
and device surfaces. Interfacial
adhesive and abrasive events coupled with drying of tissues in the operative
field produce potentially serious tissue damage and consequent post-operative
complications such as adhesions of the peritoneum or pericardium.
Our research in this area emphasizes the synthesis, properties, and
evaluation of ionic and neutral hydrophilic polymers and the formulation of
solutions for the protection of tissue surfaces during surgery, and prevention
of postoperative adhesions. Studies
also involve films, gels, and solutions of polysaccharides, proteins, and
synthetic polymers for tissue protection in all types of surgery and for the protection of
bioprostheses during harvesting and handling
2.
SURFACE MODIFIED VASCULAR GRAFTS AND STENTS
Although large-diameter woven Dacron and microporous Teflon (Goretex) vascular grafts (>5-6mm) have been used with some success for many years, there are no small diameter grafts (less than 4 mm) which remain patent for long periods of time. A great deal of research has focused on polymers with reduced thrombogenicity and on vascular endothelial cell seeding but with relatively little clinical success to date. Our studies are aimed at more bioacceptable polymer surface modifications which may incorporate selected proteins, polysaccharides, phospholipids, basement membrane proteins, growth factors, smooth muscle cell inhibitors, endothelial cell receptor polypeptides, cytokines, and various other bioactive molecules. An important thrust of this research is to produce unique, highly adherent, thin silicone coatings. These have been developed using novel silicone surface coupling chemistry which is applicable to both Dacron vascular grafts or metal (e.g. stainless steel) endoluminal stents. Research is also devoted to concepts for fixation of newer stent-graft implants, and to electrochemical surface polymerization processes, use of novel phospholipids (in collaboration with Japanese research groups), and a novel PLAD technique (Pulsed Laser Ablation Deposition) for modifying surfaces of implants with novel crosslinked polymers, i.e. silicones or PVP. Major goals are to improve blood compatibility, to provide superior substrates for overgrowth of vascular endothelium, to inhibit the thrombogenicity and long-term intimal hyperplasia for small diameter vascular prostheses, and and to minimize the major complication of restenosis for stents. Studies encompass new polymerization processes, surface characterization, in vitro cell and protein adsorption, and animal A-V shunt and implant evaluations in collaboration with Medical School scientists; particularly the vascular research group directed by Dr. James Seeger, Chief of Surgery
A wide variety of catheters
in common use exhibit significant complications which are associated with the
surfaces of the balloons and tubes used for their construction.
Infection, vascular endothelium damage, and phlebitis often accompany
the use of intravenous catheters. Infection and mineral deposits
are observed for urinary catheters. Vascular
damage, blood clots and restenosis may complicate procedures involving
cardiovascular catheters. Tracheal
tissue damage and infection may occur for endotracheal tubes used in
anesthesia. The goal of this
research is therefore modification of balloon and catheter surfaces using
silicones, phospholipids, or hydrophilic polymers with various surface
polymerization methods. Since
most catheters are made of polyethylene, nylon, silicones, polyurethanes,
latex rubber, fluorocarbons or PVC, these
have been the substrates of choice for study.
Hydrophilic, lubricious surfaces to
which tissues, bacteria, and inflammatory cells due not readily adhere have
been prepared. The incorporation of various bioactive agents into the surfaces
to inhibit infectious, thrombogenic, and occlusive cell growth complications
is an important aspect of this research.
4. SURFACE PROPERTIES AND ACCELERATED EVALUATION OF IMPLANTS
Stemming from our
earliest ophthalmic biomaterials studies, we have pioneered the development of
chemical, physical and biological methods for evaluating all types of implant
polymers and surfaces. Sophisticated
analytical facilities are available, many of which are unique to our
laboratory, including: (a)
Fourier Transform Infrared Spectroscopy (FTIFi/ATR), (b) X-ray Photoelectron
Spectroscopy (XPS/ESCA), (c) Low Voltage SEM, (d) Hydrogel Structural Analysis
by TEM with Heavy Metal Precipitation, (e) Tissue Abrasion Damage
Instrumentation, (f) Atomic Force Microscopy with Nanoscratch, Nanoindentation,
and Friction capabilities for wet and dry polymer or tissue surfaces, (g)
Quantitative Surface Adhesion and
Spreading of Cells such as Epithelial, Endothelial, Monocytes, Macrophage, and
Platelets. Accelerated Animal Implant Biocompatibility
Tests (e.g. using anterior chamber ocular implants in an autologous rabbit
lens cortex induced inflammation
model) have also been developed to afford a unique capability for evaluation
of implant materials.
5. HYDROGRAFTTM
HYDROPHILIC POLYMER SURFACE MODIFICATION
and long-term complications
due to undesired tissue interactions, e.g, chronic inflammatory processes and
cell adhesion by lens epithelial cells and giant cells.
Reduction in postoperative inflammatory reactions has been demonstrated
in animal studies. This permanent IPN-type surface modification can
significantly improve implant performance and achieve a greater margin of
safety, especially in high risk and complicated ocular implant cases. This advanced surface modification technology is also unique
in achieving uniform nanofilms on highly complex device geometries.
Modifications with vinyl-functional phospholipids to create more
natural “biomimetic” surfaces have also been developed.
Numerous university patents cover all aspects of this technology and
have been licensed to several medical device companies.
A notable clinical product example which has FDA approval is the
development of improved silicone punctum plugs for the treatment of the
potentially serious ocular problem of “dry eye”.
The trademark “Surface Insulated” has been applied to these
products by Advanced Vision Sciences Corp
6. BIOCOMPATIBILITY OF IMPLANTS AND DEVICES
A comprehensive program is in place for evaluating polymer biocompatibility using surface analyses, optical and electron microscopy, and in vitro and in vivo studies. Special emphasis is devoted to intraocular lens implants, vascular grafts and stents, and various soft tissue prostheses (i.e. silicone mammary implants) including evaluation of properties and failure analyses for explanted devices. Implant studies have been conducted under GLP protocols for FDA applications. Studies encompass rabbit, rat, mouse and canine implants; histopathology of human and animal implants; cell culture and cell-polymer surface interactions; quantitative tissue-polymer adhesion and tissue damage measurements; development of improved surgical methods and instrumentation; and accelerated implant testing.
7.OPHTHALMIC POLYMERS WITH IMPROVED MECHANICAL AND OPTICAL PROPERTIES
With the change in ocular
implant technology to rigid lenses to flexible-foldable polymers, studies have
been devoted to improved Hydrogels, Silicones, and low Tg Acrylics
with greater strength and toughness and with refractive indexes of >1.48.
More efficient vinyl-functional UV absorbers for covalent binding to
ocular lens polymers have also been developed.
Methods to control and measure hydrogel pore structure, which can be
important for implant and contact lens deposit formation, have been examined
and we have pioneered the use of Atomic Force Microscopy for examining the
morphology of dry and wet ocular polymer surfaces.
Hydrophilic radiation surface modification of hydrogels has yielded
“super-hydrophilic” hydrogels and an unusual method was developed to
prepare "hydrophobic hydrogels."
Surface analysis of contact lens polymers by AFM methods have shown
unique pore and surface structures which are clearly affected by manufacturing
processes and wear conditions. Fundamental
studies of lens-cornea interactions using AFM have also indicated new
mechanisms by which contact lens damage to the corneal epithelium may occur
and suggest approaches to improvements in contact lens materials.
8. LOW-COST/HIGH PERFORMANCE OPHTHALMIC VISCOELASTICS
Viscoelastic polymer solutions are widely used to separate and protect fragile tissues, and maintain the shape of the eye during cataract surgery and intraocular lens implantation. Improved materials have been studied as well as concepts for 2nd generation materials. Anionic polysaccharides similar to HA (hyaluronic acid) but having much lower cost and greater stability (e.g. carboxymethylcellulose - CMC), are of particular interest. Animal studies suggest that CMC compositions with properties like those of HA products can be autoclave sterilized and exhibit good shelf-life. Molecular weight-composition effects have been examined and results suggest methods for tailoring properties such as (1) shear thinning, (2) “stickiness”, and (3) tissue wetting. Concepts have been developed for beneficially incorporating drugs into these biomaterials to produce “medicated devices”. Additional research with gamma-polymerized NVP has also produced unique gel-like PVP polymers of interest for artificial vitreous replacements for the eye and for retinal tamponades.
9.
SURFACE MODIFICATION OF OCULAR IMPLANTS
We demonstrated 25 years ago that damage to sensitive tissues of the eye can result from a biophysical phenomenon; intraoperative contacts between hydrophobic plastic ocular implant surfaces and tissues such as the corneal endothelium during surgery. Instrumentation has been developed to quantitatively measure the force of such adhesion and the extent of damage to the corneal endothelium and iris. These findings led to the clinical introduction of intraoperative viscoelastic polymer solutions and new research aimed at the development of hydrophilic graft polymers to achieve more bioacceptable implant surfaces. Improved Intraocular Lenses (IOLs) which also exhibit valuable anti-inflammatory properties have been developed. Application of this technology to Phakic Implants (for refractive surgery), Foldable Lenses, Punctum Plugs, and Intracorneal Lenses has become important an important aspect of this research because of their clinical potential. Studies now emphasize synthetic methods to prepare improved Hydrophilic and Lipid modifications of PMMA, Silicones, and flexible Acrylics. Incorporation of various drugs into these polymer surfaces represents a second generation product opportunity.
10. SILICONE BREAST IMPLANT RESEARCH
Studies have been devoted to the physical, chemical, and biological properties of silicone breast implant gels and shells with emphasis on the evaluation of changes which occur in vivo that can lead to implant rupture and such local clinical complications as pain, hardness, disfigurement, chronic inflammation, and frequent reoperation. Studies encompass surface analyses, effect of silicone fluid swelling of PDMS elastomer shells on properties, analysis of gel compositions, examination of explanted prostheses, tear and tensile strength changes, the prevalence of shell failures and the frequency of additional surgeries. The first large retrospective meta-analysis of time-dependent failure of silicone gel implants was conducted and published. That data base and analysis has now been expanded to encompass data for almost 10,000 explants from 42 different studies. New polymer gels which might avoid the complications associated with silicone gel implants have been synthesized for evaluation. Hydrophilic polymer surface-modified fiber-reinforced silicone envelopes which may also be designed to locally release anti-fibrotic drugs are of interest to inhibit rupture, reduce fibrous capsule formation, and silicone-related complications. In connection with this research, a rabbit mammary implant model using miniature prostheses was developed for pre-clinical implant evaluations
11.
LOCALIZED AND CONTROLLED DRUG DELIVERY USING MICROSPHERE CARRIERS
AND AFFINITY BINDING LIGANDS
Major advances in immunotherapy and chemotherapy and delivery of antibiotics, hormones, enzymes, antibodies, antigens and other therapeutic or diagnostic agents will come from development of biopolymer drug carrier and targeting systems. Research here is devoted to a number of new approaches for localized and controlled drug delivery. Of specific interest are novel protein and polypeptide microspheres (MS) as efficient drug carriers for systemic or local administration of cytotoxic cancer drugs, antiviral agents (i.e. for HIV or hepatitis), more potent antibiotics, or labile biopolymer drugs such as growth hormones, TPA, therapeutic enzymes, etc. Versatile and stable MS compositions are also of potential value for improved treatment of rheumatoid arthritis, vaccine adjuvant systems, and macrophage activation and treatment of parasitic disease based on the avid uptake of these MS by phagocytic cells. Novel vaccines, drug targeting and diagnostic uses are facilitated by the ease of modification with various monoclonal antibodies, antigens, immune modulators and other proteins, polysaccharides, and polynucleotides. Parallel studies deal with the synthesis and properties of biodegradable films and gels for local superdose delivery of antibiotics and cytotoxic drugs to moist cavities of the body. At this time, to avoid the severe problems associated with conventional systemic chemotherapy, the primary focus of current research is on micron size microsphere-drug compositions designed for preoperative immuno-chemotherapy of breast cancer by intratumoral injection followed by surgical resection of the treated tumor mass. Animal model studies have yielded promising preclinical results for guinea pig hepatomas, rat Lewis lung carcinoma, mouse ovarian tumors, and a murine mammary adenocarcinoma. An invited comprehensive review of Intratumoral Chem-Immunotherapy was prepared for J Pharm & Pharm. Another intriguing therapeutic opportunity which remains to be studied is that of nanosphere-drug compositions designed for “Trojan Horse” intracellular uptake of antiviral drugs for safer and more effective HIV and Hepatitis treatment and for improved plasmid delivery in gene therapy.
12. MICROSPHERES FOR CELL SEPARATIONS
Various affinity (“targeting”) ligands are readily attached to protein microsphere systems. This makes them ideal for a variety of cell separation processes such as (1) hybridoma cell separations for more better and more highly automated selection of cells with particular DNA vectors, (2) more efficient separation of immune cells for bone marrow transplantation and immunotherapy, and (3) stem cell separations for tissue regeneration therapies. This technology promises to be most versatile using magnetic microspheres for gentle high yield magnetic separation of fetal cells, T-cells, and stem cells which may yield advanced diagnostic and therapeutic applications.
13.TISSUE-PROTECTIVE SOLUTIONS FOR HARVESTING CELLS AND BIOPROSTHESES
Current harvesting and
handling methods for bioprosthetic tissues (i.e. human homografts and porcine
heart valves) for bioprosthetic implants can result in tissue damage due to
oxidative and enzymatic degradation as well as mechanical damage due to
manipulative abrasion and desiccation. Even
with tissue "tanning" with glutaraldehyde, current practices can
adversely affect mechanical and biological properties of tissues; e.g. long
term biomineralization. This
research is aimed at showing that handling of bioprosthetic tissues using
tissue-protective polymer solution coatings can inhibit tissue trauma and
thereby improve the performance and implant life of fragile tissue prostheses;
i.e. corneas, heart valves and vascular grafts.
These studies principally involve the evaluation of anionic
polysaccharides such as hyaluronic acid, chondroitin sulfate,
carboxymethylcellulose, and hydrophilic synthetic polymer solutions which are
bioacceptable and have been shown to protect tissue surfaces from manipulative
damage during surgery in combination with metabolically beneficial nutrients
and antioxidants. Improved
solutions for use in tissue reconstruction to maintain cells during
harvesting, for ex vivo culture, and for cell implantation are also potential
applications.
14. WOUND HEALING,
CELL-SURFACE INTERACTIONS, AND TISSUE REGENERATION
The fundamental understanding and control of wound healing processes is central to numerous opportunities for major advances in health care. This research has been devoted to clarifying the role of the various biochemical agents involved in acute postoperative healing processes. These processes involve fibrin formation, fibrinolysis, fibroblast infiltration and collagen synthesis, production of inflammatory agents and cells (i.e., cytokines, macrophage, TGF-beta), adhesion and spreading of cells, etc. These studies are inherently multidisciplinary requiring the collaboration of cell biologists, biochemists, surgeons, and biomaterials scientists.
With UF Medical School
scientists, i.e. Dr. N. Chegini’s group in OB/Gyn, we participate in a
unique industry sponsored multi-center wound healing research program which
also involves collaboration with scientists at Wayne State University,
Gothenburg University in Sweden, and a major biotechnology company.
Related to this research, to tissue repair, and to wound healing
studies in general is the exploration of surface charge effects on tissue and
biomaterial surfaces to determine the influence of electric and magnetic
fields upon acute and chronic tissue regeneration phenomena.
Such research is also relevant to such important clinical problems as
restenosis following angioplasty and stent placement, small diameter vascular
graft patency and intimal hyperplasia
15. NERVE
TISSUE REGENERATION AND REPAIR
One of the newer and most intriguing research projects is
a collaboration with the UF Brain Institute and the research group of W. J.
Streit which is directed at the regeneration of functional nerve cells and the
repair of damaged of nerve tissues. UF
concepts involve implantation of microglia/macrophage on microporous
bioerodable polymer substrates as scaffolds to bridge damaged nerve tissues,
e.g. for spinal cord repair. A
novel approach has been the development of phospholipid-polysaccharide
compositions which have shown considerable promise as nerve cell substrates.
Funding for this research by the Christopher Reeve Foundation is
facilitating animal implant studies for proof of concepts and preclinical
trials. The figures represent the
histology of rubrospinal tract lesion (7 week survival) acutely treated with
an implant inundated with microglia. Panel A depicts fluorogold retrograde
labeled fibers, and Panel B depicts neurofilament + fibers both centrally
positioned within the implant.
REPRESENTATIVE RECENT PAPERS AND PUBLICATIONS
1.
“Polymer Solutions and Films as Tissue-Protective and Barrier
Adjuvants”, Chapt. 43 in Peritoneal
Surgery, Springer-
Verlag, 1999
2.
“Silicone Gel Breast Implant Failure and Frequency of Additional
Surgeries: Analysis of 35 Studies Reporting the
Examination of More Than 8000 Explants”, J Biomed Materials Res -
Applied Biomaterials, 1999: 48: 354-364
3. “Kinetics
of Dexamethasone Release from Silicone Coatings on Vascular Devices”, Trans.
25th Annual Mtg. Soc. Biomaterials,
1999: 395
4.
“Time Dependent rTGF Enhanced Adhesion Formation in a Rat Cecal
Abrasion Model , Trans. 6th World Biomaterials
Congress, 2000: 1095
5. “Phospholipid
and Silicone Modification of Metal Implant Surfaces by Electropolymerization”,
ibid., p. 171
6. “Modification
of Metal Implant Surfaces by Electropolymerization Using Hydrophilic Vinyl
Monomers”, ibid., p. 1528
7. “Effect
of Loading Method on Drug Content and In
Vitro Release of Mitoxantrone from Albumin Microspheres”,
8. “Advances
in Biomaterials for Implants, Devices, and Localized Drug Delivery: Problems
and Opportunities”,
9.
“Silicone Breast Implant Failure: Analysis of Literature Data for
More Than 8000 (>9600) Explants”, 68th Annual Scientific
Meeting of the Am Soc Plastic
Surgeons, New Orleans, October 1999; Plastic Surgical Forum 1999; XXII:131
10.
“HydrograftTM Surface Modified Ocular Implants for More
Biocompatible Phakic Lenses, Foldable IOLs, and Implants for
Localized Drug Delivery”, Annual Meeting Am Soc Cataract &
Refractive Surgery, Boston, May 2000
11.
“Silicone Modification of Biomaterials Surfaces by Pulsed Laser Ablation
Deposition (PLAD)”, Trans. 6th World
Biomaterials Congress 2000:168
12.
“Hydrograft Surface Modified Ocular Implants for More Biocompatible Phakic
Lenses, Foldable IOLs, and Implants for
Localized Drug Delivery”, Am Soc Cataract Refractive Surg, May 2000,
Boston
13. “Bioactivity and Drug Delivery from Modified
Polymer Surfaces”, Proc Surfaces in Biomaterials Symp 2000: 183-190
14.
“Opportunities for Axon Repair in the CNS: Use of Microglia and Biopolymer
Compositions”, in Microglia in the
Regenerating and Degenerating
CNS,
ed. J Streit, 2001 Springer-Verlag, NY
15. “Future Directions in Breast Implant
Surgery”, in Clinics in Plastic
Surgery, ed. M Habal, 2001 WB Saunders, Philadelphia
16. “Microsphere-Drug Compositions for Local
Chemo-Immunotherapy”, Trans Soc Biomaterials 2001: 288
17.
”Intratumoral Cancer Chemo-Immunotherapy: Opportunities for Nonsystemic
Preoperative Drug Delivery”, review in