Polymers as Biomaterials PDF

Polymers as biomaterials Biodegradation mechanisms Common synthetic, bioabsorbable polymers and their copolymers Common (modified) natural, bioabsorbable polymers BBT.034 Medical Biomaterials, Lecture 5...

Polymers as biomaterials Biodegradation mechanisms Common synthetic, bioabsorbable polymers and their copolymers Common (modified) natural, bioabsorbable polymers BBT.034 Medical Biomaterials, Lecture 5 University Instructor Maiju Juusela 1 Thank you for your input to Moodle task! Huge number of excellent questions  some of them will be addressed today and some of them next Tuesday We still can’t cover all of them If you have interest towards biomaterials and still have BSc thesis ahead, many of these questions could be formulated to a topic Today our focus will mostly be on bioabsorbable polymers, next week we’ll try to recap other material groups a bit ending up to composites Note! Some assignments in Moodle require manual evaluation  everyone still have 0p e.g. for Interactions related assignments. Metals –self study materials will also be opened so that they can be reviewed. 2 Polymers as biomaterials 3 Classification of polymers According to the properties Biostable polymers Bioabsorbable polymers According to the origin Natural polymers Modified natural polymers Synthetic polymers 4 Classification of biostable polymers More complicated structure, Mechanical properties, Thermal resistance… & increase in price Mass production  Technical / Engineering  Specialty polymers Used amount No need to learn the details of each individual polymer! Good to understand the variety 5  Why polymers in medicine? Variety of compositition Variety of properties Variety of available forms (solid, elastic, hydrogel...) Ease fabrication into complex shapes and structures sheets, fibers, powders, films... Reasonable costs Biodegradation And why not? Much lower strength and moduli than metals and ceramics Usually not used in load bearing applications. However, the properties are sufficient for numerous other applications. 6 Biodegradation 7 Why bioabsorbable implants are used in Medical Applications? Avoidance of removal surgery No permanent metal implant in the body for patient No risk for the long-term complications No long-term implant palpability or temperature sensitivity No growth disturbance in children No stress shielding Avoiding the trauma after the traditional implant removal Patient satisfaction (less pain, avoiding operations) New treatment and fixation options New properties which are not present with metals Easier reoperations No imaging interference Reduced overall cost for surgeon 8 Definitions Biodegradation breakdown of a material mediated by a biological system Bioabsorbable / bioresorbable capable of being degraded or dissolved AND subsequently metabolized within an organism From the book Biomaterials Science: An Introduction to Materials in Medicine (link available in Moodle) 9 A couple of minutes to discuss “Many of the polymers are considered plastics, and usually plastic degradation cause microplastic, which are usually said to be dangerous or toxic. So, how is it safe that polymers can be degraded in body without causing bad reactions?” “I would like to hear more about the process by which the bioabsorbable or bioresorbable polymers are metabolized in the body. It seems like a great concept but are the polymers truly metabolized or can there be residue left from them?” “There has been talk of microplastics in the body… Is this relevant only for the "biostable" polymers that have been dissolved into microparticles? But if they are biostable, wouldn’t they cause no harm in the body even in microparticles?” 10  There are two major biodegradation mechanisms: HYDROLYTIC and ENZYMATIC degradation The goal of both types is usually to produce relatively low-molecular weight products that are water-soluble  cleared by the body’s natural processes. http://www.inion.com/patienteducation/Orthopaedics/en_GB/Patient_education_ankle/ 11  What happens inside the implant? 1. Molecular weight of the implant reduces when water molecules cut the polymer chains of the material shorter. The mechanical strength of the material remains unchanged until enough chains have been cut. 2. When water continues to cut the polymer chains even more, the strength reduces but The initial mass of the implant remains unchanged until the material becomes so weak that it starts to fragment. 3. The actual metabolic elimination of the implant starts first after the fragmentation of the material first then the mass of the implant starts to decrease. ”Breaking the wall” 12  Hydrolytic degradation Hydrolysis is any chemical reaction in which a compound is converted into another compound by taking up water. Chain Scission – water molecules facilitate the cleavage of certain bonds (e.g. O and/or N) within the macromolecule. Example: Polylactide -> chain scission to oligomers that enter the cells -> lactic acid -> oxidation -> puryvate -> acetyl coenzyme A (CoA) -> citric acid cycle -> CO2, H2O 13  Hydrolysis 14 Water breaks up bonds Molecular weight decreases  mechanical properties decrease Polymer mass loss Degradation into monomers that are metabolized Erosion (mass loss) caused by hydrolysis Bulk erosion Surface erosion 15  16 Bulk erosion Surface erosion Water penetrates the entire Water penetration to the polymer bulk causing polymer is only slightly faster hydrolysis throughout the than the degradation of the entire polymer matrix polymer Water diffusion is faster than Polymer volume is reduced hydrolysis layer by layer by time, until it eventually disappears Molecular weight does not change during the degradation (ideal situation)  17 Autocatalytic degradation As poly-α-hydroxyacids (polylactide, polyglycolide) degrade, the degradation products are acidic Acidic degradation products catalyse the degradation reaction further  As a result, polymer degrades faster inside than outside Because the degradation products can dissolve to the surrounding medium from the surface of the polymer but not from the inside of the material. Surface Bulk Autocatalytic Woodruff and Hutmacher, Progress in polymer science, vol 35 (10) 2010, 1217-1256 18 Some questions from Moodle related to bioabsorbables How can the polymer biodegradation process be predicted and designed? Difficulties in predicting the degradation rate if it can vary between individuals? It was mentioned that bioabsorbable polymers have more strict requirements for biocompatibility, so what exactly needs to be tested? One that came to mind was how you know how fast a bioabsorbable polymer degenerates in the body. What kind of testing is used to determine the rate? How are these polymers tested for being bioabsorbable? In the materials it was said that some polymers can be toxic when degrading. 19  How long is the degradation time? Length of the degradation time depends on: Material properties Hydrophobic vs. hydrophilic Polymer structure/morphology Molecular weight Manufacturing Process Process parameters Sterilization method Implantation site Inside vs. outside bone Thickness of the covering soft tissue layer Local vascularity/blood circulation + Individual differences in metabolism and/or local vascularity / blood circulation! 20 How the degradation behavior is tested? Combination of different methods is required! Laycock, 2017 | 21  Enzymatic (enzymatically catalysed) degradation Enzymes (proteins present in tissues) reaction products have a particular affinity for certain chemical groups present in polymers. substrate enzyme  catalyze biochemical reactions (hydrolysis, oxidation...) cofactor Outside or inside the cells Molecular chains are cut to smaller pieces May occur at the later stages of degradation for materials that are originally degrading by hydrolysis only 22  Hydrolytic and enzymatic degradation 23 Both degradation mechanisms produce low molecular weight and water soluble products that are metabolized through body’s normal metabolism The mechanisms may also exist in combination  Common synthetic, bioabsorbable polymers 24 Bioabsorbable Synthetic Polymers Polyesters Poly(glycolic acid) PGA (homopolymer) PGA Poly(lactic acid) PLA (homopolymer) Poly(caprolactone), PCL (homopolymer) PLGA Poly(butylene succinate), PBS (copolymer PLA obtained from succinic acid and 1,4- PCL butanediol) Poly-(lactic-co-glycolic acid) (copolymer) Other copolymers PBS 25  Polyglycolide (PGA) Synthetic bioabsorbable polymer The simplest of the poly--hydroxyacids 2n Glycolic acid 26  Polyglycolide (PGA) Highly crystalline high melting point low solubility in organic solvents. PGA was used in the development of the first totally synthetic, bioabsorbable sutures (Dexon since 1970) 27  Polyglycolide (PGA) Degradation involves both hydrolysis and enzymatic degradation  degradation product is glycolic acid Can be eliminated by the metabolic pathway as carbon dioxide and water. Bulk PGA degrades and gets absorbed in approximately 3 – 6 months faster than PLA because PGA is more hydrophilic Copolymerization of glycolide with more hydrophobic lactide results in wide range of polymer properties and possible applications http://www.sciencebrainwaves.com/ultra-ever-dry/ 28 Biodegradable Synthetic Polymers - Polylactides Polymers obtained from different isomers (PLLA, PDLA, PDLLA) and copolymers have different properties PLLA PDLA PLA Different degradation rate, physical and chemical properties – can be adjusted as needed and processed in multiple ways BUT Polyesters have a low degradation rate, originating acidic products (pro-inflammatory) Significantly hydrophobic (many attempts to improve surface properties) (a) poly(L-lactide) (PLLA); (b) poly(D-lactide) Low cell adhesion, low bioactivity (PDLA); (c) poly(D, L-lactide) (PDLLA). 29  Polylactide (PLA) PLA degrades by bulk hydrolysis of the ester bonds. The degradation product is lactic acid, which is a normal byproduct of anaerobic metabolism in the human body. The complete degradation and mass absorbtion of the certain forms of bulk PLA can take 3 – 5 years (this is much longer than with PGA). Applications Sutures Orthopedic implants (screws, plates, pins), Tissue engineering Drug delivery Cranio-maxillofacial (CMF) surgery 30 https://askelhealthcare.com/products  Poly--caprolactone (PCL) O O Catalyst O * O (CH2)5 C n * Heat Caprolactone Poly(caprolactone) Degrades relatively slowly Hydrolysis is accompanied with enzymatic degradation at later stage Slower degradation and mass absorption than for PLA Can be copolymerized with lactide, glycolide etc. Well mixable with other polymers 31  Poly--caprolactone (PCL) Degrades relatively slowly Hydrolysis is accompanied with enzymatic degradation at later stage Slower degradation & mass absorption than for PLA CL can be copolymerized with lactide, glycolide.. Well mixable with other polymers Ethicon Inc. Application areas Porous and elastic TE scaffolds Synthes Ltd. Capronor (capsule releasing contraceptive hormone) Sutures (Monocryl) R&D in tissue engineering and drug delivery Good permeability for drugs with small molecular size Genoss Ltd. 32  Poly--caprolactone (PCL) 33 …More applications Woodcast Biodegradable cast Woodcast is non-toxic, mouldable & remouldable and made from clean wood and biodegradable plastic. (https://woodcast.com/) https://woodcast.com/ Copolymers 34  Copolymers 35 Homopolymer properties are often not good enough for medical applications Copolymerization offers a way to modify the properties Mechanical Degradation Crystallinity  Copolymers 36 Polymer’s response to an applied stress or strain depends on the strain rate, temperature and time period of loading. This viscoelastic behavior can be modified by blending different polymers or copolymerizing different monomers Typical copolymer materials for lactides are e.g. glycolide and trimethylene carbonate  What was wrong with the early generation biodegradables? PGA (homopolymer) Semi-crystalline (up to 55%) but hydrophilic Fast degradation Rapid strength loss Higher risk of inflammation with adult patients PLLA (homopolymer) High-crystalline (up to 75%) and hydrophobic Bulky fragments of a highly crystalline PLLA interference screw 20 months Very slow, unpredictable degradation after implantation compared with a non used specimen Crystalline residue – late inflammatory response References: Middleton et al 2000, Andriano et al 1994, Böstman et al 2000, Radford et al 2005, Warden et al 2008, Kwak et al 2008. 37  38 Poly(lactide-co-glycolide) (PLGA) Belongs to the most studied bioabsorbable polymers Properties are well-known Biocompatible polymers Processing is simple Degrades to lactic acid and glycolic acid Properties can be modified by Changing the comonomer ratio in the copolymer, lactide is more hydrophobic than glycolide By choosing the lactide monomer: L,D or LD  Poly(lactide-co-glycolide) (PLGA) Orthopedic implants Screws Nails Pins www.bioretec.com 39  Poly(lactide-co-caprolactone) (PLCL) 40 Flexible Good drug release properties Tailorable: properties depend largely on the comonomer ratio Copolymers often degrade faster than their respective homopolymers Synthes Ltd.  Materials Selection L-lactide Strength, longer lasting D,L-lactide Flexibility, disrupts crystallinity Glycolide Fast resorption TMC (trimethylenecarbonate) Malleability Unique handling, strength and degradation characteristics for different applications! 41  Summary of synthetic, bioabsorbable polymers 42 Bioabsorbable polymers are used when temporary function or support is needed Hydrolytic degradation is the most common with synthetic BPs May be accompanied by enzymatic degradation Processing methods similar to stable polymers (mostly melt processing) Variety of shapes and geometries possible, mostly without using solvents Most common bioabsorbable polymers Polylactide (PLA) Polyglycolide (PGA) Polycaprolactone (PCL) Copolymers of the former Application areas Orthopedics Controlled drug delivery Tissue engineering (Modified) Natural, bioabsorbable polymers 43 “Since many natural polymers are generally widely used in tissue engineering, but new xeno-free methods are needed because of the ethical reasons, would be nice to see how natural and synthetic polymers are produced and how synthetic polymers can replace natural polymers, or can they? What are the main challenges? Is there some kind of chemical structures, which are difficult to mimic or produce? ” “There were many disadvantages for natural polymers. Are they how commonly used in medical field?” “I would wish to hear how the natural, bioabsorbable biomaterials are modified to fit the human body.” “I didn't quite catch how some residues can make natural polymers toxic? “ 44 Natural Polymers Advantages Biocompatible Enable cell adhesion Facilitate cell growth and tissue remodelling Sustainable sources 45 Natural Polymers Disadvantages Limited physical and mechanical stability Challenges with processing Unsuitable for load-bearing applications Can induce an immune response Batch-to-batch variation (meaning?) Degradation more difficult to predict Strategies to improve their properties, such as mechanical reinforcement 46  Why growing interest in Natural polymers? 47 Growth of tissue engineering Continuous search for perfect materials for implants increased biocompatibility increased cell adhesion, migration and proliferation enzymatic degradation considered as a good way for biodegradation Additionally, new materials are also needed in everyday (non-medical, non-implantable) applications starch-based plastic bags paper coating with compostable, biodegradable plastics Natural Polymers Collagen: main protein of the ECM Gelatine: low MW derivative of collagen Fibrin: insoluble network of polymerized blood proteins (fibrinogen and thrombin, involved in clotting) Elastin: highly elastic protein in connective tissue Hyaluronic acid: anionic glycosaminoglycan (important polysaccharide of the ECM) Chitosan: polysaccharide derived from chitin (deacetylation) Alginate: polysaccharide obtained from the cell walls of brown algae Silk fibroin: fibrous protein produced mainly by silkworms and spiders 48 How to obtain natural polymers? Do not exist in nature as ready-for-use Extraction, purification and often also modification needed Series of different treatments e.g. with chemicals and heat Recombinant proteins as an option Sustainability ”Biopolymer” term used confusingly (natural polymer / raw material originates from nature / bioabsorbable..) Available in Moodle 49  Natural polymers 50 Applications... wound covers coatings of implants, catheters and stents bone grafts cosmetics hydrogels plasma expanders drug release tissue glues sutures tissue engineering scaffolds  cartilage, bone, skin, tendons, blood vessels  PLGA- collagen Strategies to achieve appropriate composite mechanical properties AND bioactivity: Creating composite materials Poly(glycolic acid) PGA + Gelatin + Elastin Poly(glycolic acid) PGA + Collagen type I + Elastin Polymers coated with fibronectin, laminin, RGD, etc. Arginine-Glycine-Aspartate Chen et al (2003), The use of a novel PLGA fiber/collagen composite web as a scaffold for engineering 51 of articular cartilage tissue with adjustable thickness, J Biomed Mater Res A., 15;67(4):1170-80. Hydrogels 52 Hydrogels Hydrophilic polymeric network that swells in water without being dissolved in it. They can be used as biomaterials because they are soft and rubbery and contain large amounts of water. - Repair of corneal defects - BioMediTech - Hyaluronic acid and collagen hydrogels - Adipose stem cells Koivusalo, Karvinen et al (2018), Materials Science and Engineering C, 85, 68-78 53 Hydrogels Synthetic polymers Natural polymers Blends or mixtures of different polymers Typically degraded by hydrolysis or enzymatic degradation Properties can be adjusted by: Highly Hydrated – mostly water High swelling ratio, can contain Polymer composition >99% water Polymer concentration (and amount of water) Low volume fraction of polymer Degree of cross-linking (low amounts of polymer needed) Very low interfacial energy in water Low contact angle with water 54  Hydrogel applications Carriers for drug delivery Wound dressings Contact lenses Tissue engineering scaffolds Injectable hydrogels Liu et al (2017), Bone Research, 5, 17014 56  Summary – (Modified) natural polymers 57 Polymers derived from nature (animals, plants…) As such or modified Natural polymers often offer good biocompatibility and degradability The main disadvantages are Poor mechanical properties Batch to batch variations Difficulty of processing  58 Future.. “I've been thinking about the future of implants, especially considering the fact that we currently use materials like metals in the body. Are we moving toward a future where metals will no longer be necessary? Considering how for example metals have corrosion overtime. If it becomes possible to grow bone or other tissues from a patient's own cells and use them as implants, wouldn’t this approach offer the best compatibility and long-term success? It seems that using the body’s own tissue would provide the most accurate, biocompatible, and sustainable solution.” General announcements MED-EL visit 30.9.-1.10. Lecture next Tue 1.10. Recap on the course contents / Maiju Electrophysiological impacts of implantation and foreign-body reactions with cochlear implants / Dr.Tech Marko Takanen, Advanced Research Engineer, R&D Clinical Systems, MED-EL Hands-on sessions 30.9.-1.10. (max. 45min/group, sign-up in Moodle) Exam on Fri 18.10. at 9-12 in Hervanta Enrolment open in SISU until 11.10. Questions will be in English, answering allowed in English or in Finnish 3 questions, 12p each (18/36p required to pass) 59 Thank You! 60