Biodegradable Polymers

Nomenclature There is a confusion between biodegradation, bioerosion, bioabsorption and bioresorption! Degradation: Typically= Cleavage of covalent bonds Erosion: Typically= physical change (size, shape, mass)-dissolution ex: sugar dissolves in water but not degrades! Biodegradable: Degradation by a biological agent enzyme, microorganism, cell,… Bioerodable: Erosion under physiological condition physical (ex: dissolution) and/or chemical (ex. Backbone cleavage Bioresorbable /Bioabsorbable: may dissolve and/or degrade and products are removed from the body cleared by kidneys, phagocytosis, etc

Why degradable? No need to remove (no second surgery) When needed only for a transient period of time Reduce chronic foreign body response Body’s natural material is better and safer Allows normal tissue function to take over Allows gradual healing/tissue to gain strength Eliminates additional surgery to remove an implant after it serves its function Ideal when the “temporary presence” of the implant is desired replaced by regenerated tissue as the implant degrades orthopaedic fixation devices (requires exceptionally strong polymers) adhesion prevention (requires polymers that can form soft membranes or films) temporary vascular grafts (development stage, blood compatibility is a problem Degradation rate must match the healing time of the tissue Must have non-toxic degradation products

Applications Drug delivery Tissue scaffolds Stents Staples Sutures Adhesives Fracture fixation (requires exceptionally strong polymers) adhesion prevention (requires polymers that can form soft membranes or films) temporary vascular grafts (development stage, blood compatibility is a problem

Main types of degradable implants the temporary support the temporary barrier the drug delivery device multifunctional devices Tissue engineering

Temporary Support provides mechanical support until the tissue heals tissue weakened by disease, injury or surgery healing wound, broken bone, damaged blood vessel sutures, bone fixation devices (nail, screw, plate), vascular grafts Rate of degradation = gradual stress transfer implant should degrade at the rate the tissue heals Major challange! Nothing new commercially Sutures are most widely used and most successful polyglycolic acid (PGA) - Dexon® (1970) copolymers of PGA/PLA (90/10), Vicryl® 1974 polydioxanone (PDS) 1981

Temporary Barrier Prevent adhesion caused by clotting of blood in the extravascular tissue space clotting  inflammation adhesions are most significant problems after cardiac, spinal and tendon surgery Barrier in the form of thin membrane or film Another barrier use is artificial skin for treatment of burns Stimulate regrowth of functional dermis: collagen/glycosaminoglycans Can cause pain, functional impairment Film adhacent to adhesion prone tissue Artificila skin can be preseeded with fibroblast!

Biodegradable: Drug Delivery Most widely investigated application PLA, PGA used frequently Polyanhydrides for administering chemotherapeutic agents to patients suffering from brain cancer

Tissue Engineering Artificial extracellular matrix Provide space for cells to grow and reorganize into functional tissue Ideally: Restore lost function Maintain function Enhance function Forms: Foam Sponge BUT pore connectivity is critical! (OPEN pores) Pre-seeded with cells or not

Multifunctional Devices Combination of several functions mechanical function + drug delivery biodegradable bone nails and screws made of ultrahigh-strength PLA and treated with BMP & TGF- for stimulation of bone growth

Biodegradable: Multifunctional Devices mechanical support + drug delivery: biodegradable stents to prevent collapse and restenosis (reblocking) of arteries opened by balloon angioplasty and treated with anti-inflammatory or anti-thrombogenic agents Biodegradable intravascular stent molded from a blend of polylactide and trimethylene carbonate. Photo: Cordis Corp. Prototype Molded by Tesco Associates, Inc.

Biodegradable Polymers Variety of available degradable polymers is limited due to stringent requirements biocompatibility free from degradation related toxic products (e.g. monomers, stabilizers, polymerization initiators, emulsifiers)

FDA approved ones As of 1999: poly(lactic acid) poly(glycolic acid) polydioxanone polycaprolactone poly(PCPP-SA anhydride) degradable polymers have been approved for use in a narrow range of clinical applications

Biodegradable Polymers

Chemistry of Biodegradable Polymers Most degradable polymers are polyesters ester is a covalent bond with polar nature, more reactive can be broken down by hydrolysis the C-O bond breaks ESTER BOND

Chemistry of Biodegradable Polymers Amide link can be broken down by hydrolysis the C-N bond breaks can be spun into fibers for strength

What causes degradation? solid structural polymer --> soluble stuff and goes away Simple hydrolytic cleavage of backbone Enzymatic cleavage (biodegradation) not guaranteed same in each patient Naturally derived materials have established degradation pathways

bioerosion changes in the appearance of the device, in its physicomechanical properties in physical processes such as swelling, deformation, or structural disintegration, weight loss, and the eventual depletion of drug or loss of function. bioerosion of a solid device chemical cleavage of the polymer backbone or the chemical cleavage of cross-links or side chains. simple solubilization of the intact polymer (due to changes in pH, etc)

Degradation • Cleavage of crosslinks – Yield smaller soluble chains • Cleavage of side chains/pendant grps – Change polarity, charge, solubility • Cleavage of the backbone Chemical degradation mediated by water, enzymes, microorganisms

HOW DOES IT DEGRADE ? Bulk vs. surface • Rates vary according to : – Time (seconds -months) – In vitro, in vivo – Anatomic location – Human variability

Degradation throughout the whole sample! Bulk erosion Degradation throughout the whole sample! water enters polymer (faster than degradation rate) characteristic of hydrophilic polymers causes hydrolytic degradation component hollowed out finally crumbles releases acid groups (acid bursting)  possible inflammation (PLA,PGA,PLGA, PCL)

degradation occurs on the surface water penetration limited ! Surface erosion degradation occurs on the surface water penetration limited ! hydrophobic polymers experience surface erosion since water intake limited thinning of the component over time integrity is maintained over longer time when compared to bulk erosion surface erosion can also occur via enzymatic degradation Differ from patient to patient, tisuue to tisuue acidic byproducts are released gradually  acid burst less likely, lower chance of inflammation (poly(ortho)esters and polyanhydrides)

Before factors…… Steps of erosion/degradation water sorption reduction of mechanical properties (modulus & strength) reduction of molar mass weight loss

Factors that determine rate of erosion chemical stability of the polymer backbone erosion rate: anhydride > ester > amide hydrophobicity of the monomer hydrophobic comonomers reduce erosion rate morphology of polymer crystalline vs. amorphous packing density Polymer less permeable to water in glassy state: Tg of the polymer should be greater than 37 C to maintain resistance to hydrolysis under physiological conditions Amorphous degrades faster

Factors that determine rate of erosion initial molecular weight of the polymer fabrication process Porous, dense… presence of catalysts, additives or plasticizers geometry of the implanted device (surface/volume ratio) defects

Biodegradable Polymers: Storage, Sterilization and Packaging minimize premature polymer degradation during fabrication and storage moisture can seriously degrade controlled atmosphere facilities

Biodegradable Polymers: Storage, Sterilization and Packaging -irradiation vs ethylene oxide both methods degrade physical properties choose lesser of two evils for a given polymer -irradiation dose at 2-3 Mrad (standard level to reduce HIV) can induce significant backbone damage ethylene oxide highly toxic PLA, PGA Need to degass for long period of time before use

Biodegradable Polymers: Storage, Sterilization and Packaging Packed in airtight, aluminum-backed, plastic foil pouches. Refrigeration may be necessary

Scaffolds incubated with viable cells… No way to sterilize Prepare under sterile conditions No shelf life

Synthetic Degradable Polymers

Polydioxanone (PDS) Poly(ether-ester) Low modulus Tg: −10 - 0 °C crystallinity of about 55% Monofilment sutures 1st commercialized one Suture clips Bone pin flexibility

Polyanhydrides Most hydrolytically unstable polymer !!!! First proposed by Langer for use in drug delivery in 1993 Aliphatic ones degrade within days Aromatic ones may take years Fast surface erosion Excellent in vivo compatability Can react with amine containing drugs! But also biomolcules around the implant?! Mostly used in drug delivery (microcapsule) Gliadel was developed using the principles just outlined. Carmustine has a small effect on brain cancer patients when given systemically. The drug has limited passage through the blood brain barrier. It is relatively rapidly cleared, and its systemic toxicity (e.g., bone marrow suppression) limits dosing. CarmustineÕs mechanism of action is DNA and RNA alkylation. Once cellular DNA is alkylated, it cannot replicate, and the cell dies. Including carmustine in a PPCP-SA polymer allows the direct application of the Gliadel wafer to the surface of the tumor resection cavity. It has been demonstrated that most brain cancers recur within a 2-cm margin after resection and eventually lead to the death of the patient, not by distant metastasis, but by local growth, invasion, and compromise of brain function (3).

Gliadel® 1st commercial application: chemotherapy Brain tumor treatment patch Compression moulding of the spray-dried polyanhydride microspheres Carmustine + Copolymer of 1,3-bis(p-carboxyphenoxy propane) (CPP) and sebacic acid (SA) (degrade in 6-8 wks) Before implantation 1day after 5 day after P(CPP-SA) Carboxyphenoxypropane Sebacic acid Excreted metabolized by oxidative pathway (CO2) Gliadel was developed using the principles just outlined. Carmustine has a small effect on brain cancer patients when given systemically. The drug has limited passage through the blood brain barrier. It is relatively rapidly cleared, and its systemic toxicity (e.g., bone marrow suppression) limits dosing. CarmustineÕs mechanism of action is DNA and RNA alkylation. Once cellular DNA is alkylated, it cannot replicate, and the cell dies. Including carmustine in a PPCP-SA polymer allows the direct application of the Gliadel wafer to the surface of the tumor resection cavity. It has been demonstrated that most brain cancers recur within a 2-cm margin after resection and eventually lead to the death of the patient, not by distant metastasis, but by local growth, invasion, and compromise of brain function (3). D .S . Katti et al . / Advanced Drug Delivery Reviews 54 (2002) 933–961

Polyesters MOST WIDELY USED MATERIAL DEGRADATION BY HYDROLYSIS BUT; ACID DEGRADATION PRODUCT

Biodegradable Polymers: Hydrolysis Breakdown of a molecule in the presence of water Hydrolysis of the ester bond results in formation of an acid and an alcohol Inverse of reaction to hydrolysis is condensation (remember condensation polymerization) Hydrolysis of ester Hydrolysis of anhydride hydrolysis condensation

PLA and PGA POLYGLYCOLIC ACID Most studied and used ones! More hydrophilic highly crystalline high melting point low solubility Degrades fast !!!! Dexon ® sutures lose strength within 2-4 weeks sooner than desired used as bone screws, Biofix®

Polylactic acid More hydrophobic Slower hydrolysis D and L-PLA: differ in morphology! L(+)-PLA: semicrystalline (natural) most common mechanical applications (Good mechanical strength) sutures or orthopaedic devices D,L-PLA: Amorphous Faster degradation rate Drug delivery Homogenous distribution of drug in matrix

PLA and PGA Tailor degradation rate and mechanical strength Lactic acid decreases water uptake! VICRYL® (1974) and Polyglactin 910® (90/10 PGA/PLA) PANACRYL ® (3/97 PGA/PLA) (sutures)

Polymer Tm (°C) Tg Modulus Degr.Time (°C) (Gpa)a (months)b PGA 225—230 35—40 7.0 6 to 12 L-PLA 173—178 60—65 2.7 >24 DL-PLA Amorphous 55—60 1.9 12 to 16 85/15 DLPLG Amorp 50—55 2.0 5 to 6 75/25 DLPLG Amorph 50—55 2.0 4 to 5 65/35 DLPLG Amorph 45—50 2.0 3 to 4 50/50 DLPLG Amorph 45—50 2.0 1 to 2 a Tensile or flexural modulus. b Time to complete mass loss. Rate also depends on part geometry.

Biodegradable Polymers

Acid degradation product Issues Acid degradation product Relatively strong acids Inflamation Cells do not grow on PLA PGA that well Limited use as tissue scaffolds pKa : 3.83

Poly(caprolactone) semi-crystalline polymer slower degradation than PLA remains active as long as a year for drug delivery Low Tm (60°C) Low Tg (-60°C) Rubbery at RT Caprolactone is non-toxic Wound dressing and controlled drug delivery

Polymer Tm (°C) Tg Modulus Degr.Time (°C) (Gpa)a (months)b PGA 225—230 35—40 7.0 6 to 12 L-PLA 173—178 60—65 2.7 >24 DL-PLA Amorphous 55—60 1.9 12 to 16 PCL 58—63 - 65 0.4 >24 PDO N/A -10— 0 1.5 6 to 12 a Tensile or flexural modulus. b Time to complete mass loss. Rate also depends on part geometry.

Capronor® implantable biodegradable contraceptive implanted under skin the implant remains intact during the first year of use, thus could be removed if needed. dissolve in the body and does not require removal degradation of the poly(e-caprolactone) matrix occurs through bulk hydrolysis of ester linkages autocatalyzed by the carboxylic acid end groups of the polymer, eventually forming carbon dioxide and water

Monocryl suture was developed as a shorter-term suture. PGA/PCL (75/25) copolymer. It has been reported that the first block is a PCL/PGA (45/55) random copolymer while the end blocks are predominantly composed of PGA Biosyn suture introduced in 1995 glycolide, TMC, and p-dioxanone in a 60/23/17 weight ratio PTMC/PDO (65/35 w/w) copolymer while the end blocks are random PGA/PDO (92/8 w/w) copolymers Caprosyn, introduced in late 2002 glycolide, ε-caprolactone, l-lactide, and TMC in a 68/17/7/7 weight ratio Caprosyn loses all strength by 3 weeks and is absorbed by the body in 56 days, making it the fastest-absorbing synthetic monofilament.

Poly alkanoates polyesters synthesized and used by microorganisms for intracellular energy and C storage rate of degradation controlled by varying copolymer composition but all takes SEVERAL YEARS to be completely resorbed! used in controlled drug release, suturing, artificial skin, and paramedical disposables

Poly alkanoates: Poly(4-hydroxybutyrate) PHB crystalline/brittle Slow degradation Retains 80% of strength after 500days of implantation in vivo degradation product :hydroxybutyric acid normal constituent of human blood  biocompatible, nontoxic

Poly alkanoates: PHV, p(hydroxyvalerate) PHV/PHB: more flexible, less crystalline, more processable Biopol®: 70% PHB-30% PHV copolymer Internal suture • Heart valve- Mayer, Vacanti

polyorthoesters formulated so that degradation occurs by surface erosion drug release at a constant rate

polyaminoacids poly-L-lysine, polyglutamic acid aminoacid side-chains offer sites for drug attachment low-level systemic toxicity owing to their similarity to naturally occurring amino acids investigated as suture materials artificial skin subtitutes

polyaminoacids limited applicability as biomaterials! limited solubility and processibility difficult to predict drug release rate due to swelling polymers containing more than three or more amino acids may trigger antigenic response “pseudo”- polyaminoacids backbone of polyaminoacids altered tyrosine derived polycarbonates developed as high-strength degradable orthopaedic implants

Biodegradable Polymers polycyanocrylates used as bioadhesives (IIWW) Dental adhesive (butyl derivative) Drug delivery (newer!) use as implantable material is limited due to significant inflammatory response (formaldehyde) Very reactive monomer! Superglue!

Biodegradable Polymers polyphosphazenes inorganic polymer backbone consists of nitrogen-phosphorus bonds High thermal properties use for drug delivery under investigation