Having attended a basic course on polymers (suggested).

If not done before, attending a basic course on polymers during the course of Biomaterials (suggested).

This course enables the course of Materials for special applications (2nd year) (suggested).

1. Introduction to the Course: Definitions of biomaterials and Biocompatibility; Historic perspective of biomaterials (biomaterials generations); Multidisciplinarity.
2. Biocompatibility: Factors impacting biocompatibility (toxicity, pathogens, mechanics; cell-biomaterial interaction); Cells; Blood cells; Inflammation (acute and chronic); Foreign body reaction; Fibrotic encapsulation.The immune system; Innate immunity and adaptive immunity; Cell-mediated immunity and humoral immunity; Antibodies (immunoglobulins); T and B lymphocytes; Failure of immune system (hypersensitivity, allergy, autoimmunity and immunodeficiency); Systemic toxicity and hypersensitivity to implanted biomaterials (dose, exposure time, synergistic effects, metal ions and haptens); Blood compatibility (fibrin clot formation and resorption); Carcinogenesis associated to implanted biomaterials.
3. Biodegradable polymers. General concepts of: biodegradation, bioresorption and bioabsorption; Classes of biodegradable polymers; Biotechnologies (recombinant DNA technology and genetic engineering, PHAs). Natural biopolymers: polysaccharides (dextran, chitosan, hyaluronan, alginate); Proteins (collagen, gelatin, elastin). Synthetic polymers: Aliphatic polyesters (PLA, PGA, PLGA, PCL, PHAs, PHBs); Polyanhydrides; Polyorthoesters, Polyamides, Polyaminoacids; Polyphosphazenes. Degradation mechanisms: Degradation and erosion; Bulk and surface; Factors affecting degradation; Hydrolitic degradation and autocatalytic phenomena; Case studies. Degradation modeling (basics): Empirical, semiempirical, mechanicistic (deterministic and stochastic).
4. Tissue Engineering: History; Facts and figures; Tissue Engineering paradigm and 3rd generation biomaterials. Classifications: in vitro and in vivo Tissue Engineering; Regenerative medicine; Cell therapy; Tissue Engineering triad (cells, scaffold, signals). The cell: cell source and cell type; Stem cells: definitions (stemness, potency and differentiation); Types (embryonic, adult and induced pluripotent); Mesenchymal stem cells. The scaffold: biomaterial selection and dimensionality factors; Scaffold requirements; Scaffold factors influencing cell growth and differentiation (stiffness, architecture, porosity, pore size, pore interconnectivity, pore geometry, mechanical stability); Scaffold fabrication technologies (fiber bonding, solid free form fabrication, stereolythography, electrospinning and non-fibrous scaffolding methods). Signals: Biochemical (soluble and surface-factors); Physico-chemical (surface chemistry, biomaterial elasticity, bioreactors); Topographical.
5. Micro & Nanoparticle systems. Introduction: size and shape; Microparticles: Natural polymers (chitosan, alginate, gelatin) and bioresorbable synthetic polymers (PDLA, PLGA, PGL, POE); Biodegradation and uses; Microparticle preparation (single & double emulsion solvent evaporation, precipitation and coacervation, spray drying, ionic gelation); Industrial production (example). Sub-micrometric particles: Lyposomes and micelles. Nanoparticles: size dependent properties (noble metals, magnetic materials, quantum dots, polymers and lipids, silica, carbon, piezoelectric materials); Surface functionalization (passive absorption and bioconjugation); Nanotoxicity.
6. Hydrogels: Introduction and classifications; cross-linking and tie-points; Synthesis (Free radical, chemical, enzymatic, stereo-complex formation); Swelling (Equilibrium and Flory-Huggins theory, volume and weight degrees of swelling); Hydrogel characterization (polymer volume fraction in swollen state, average molecular weight between crosslinks, mesh size); Viscoelasticity; Solute transport (Fick's law). Biomedical hydrogels: Acrylic (PHEMA, polyacrylamides and copolymers, interpenetrating networks); PVA; PEG and PEO; Degradable (hydrolitically and enzymatically); Star-polymer and dendrimer hydrogels. Stimuli-responsive hydrogels: pH- (anionic and cationic, synthetic and natural, isolectric point); thermo- (upper and lower critical solution temperatures, PNIPAAm, zipper effect); chemically- (es. glucose); photo- ; electrically- ; mechanically-responsive (shear-thickening) hydrogels.
7. Metals and Corrosion: Biometals; Biofluids; pH in different fluids and physio-pathological conditions; Historic overview of metals in orthopedic implants (stainless steels, cobalt alloys and titanium alloys); General requirements of metallic biomaterials (corrosion, wear and fatigue); General concepts of corrosion and mass loss (Faraday's law, anodic and cathodic curves, active-passive behavior, corrosion/passivation current and potential); Toxicity and allergy to metals; Metallic-plastic supports and UHMWPE; Hip anatomy; Hip prosthesis (cemented and uncemented); stress shielding and surface finishing; PMMA cement and drawbacks; mobilization (septic and aseptic) and temporary hip prosthesis; Stainless steels (sensibilization and AISI 316L); Cobalt alloys (F75, F90, F562, F563); Titatium and Ti alloys (Ti6Al4V). Corrosion in orthopedic implants: General attack corrosion (accumulation rate in the human body); Galvanic corrosion; Pitting; Crevice corrosion; Corrosion fatigue. Oral environment (chemical composition, REDOX potential, pH, temperature variations and buffer system in saliva); Oral versus interstitial fluids; Artificial solutions (artificial saliva, Ringer solution); Dentistry; Tooth damages (dental caries, anterior and posterior teeth decay, missing/lost teeth); Tooth restorations (amalgams, fixed partial denture, removable partial denture, pergengival implants). Materials in Dentistry: Amalgams (effects of Cu, Sn and Hg); Noble metal alloys (for crowns, bridges and dentures); Base metal alloys (Co-Cr and Ni); Titanium and Ti-alloys (oral implantology, wires, moldability, Nitinol, shape-memory and super elasticity); Corrosion and opacification (galvanic pain, cariogenesis and allergy, acid-producing and sulfate-reducing oral micro-organisms). Current pathways in metallic restorations of teeth (single non-contact, two non-contact, two opposite with intermittent contact, adjacent in continuous contact).
8. Additive manufacturing for tissue engineering applications. Reverse engineering and computer assisted design (CAD). Microfabrication technologies: Selective laser sintering (SLS); Stereolithography, 2 photon polymerization (2PP); 3D plotting; 3D Printing; Fused deposition modeling (FDM); solution or melt electrospinning. Examples of applications in bone, cartilage, eardrum and pancreatic beta-islet encapsulation. Examples of complex tissue regeneration and Bioprinting.
9. Electrospinning and electrospray. Practical case. Preparation of polymer solutions. Principles of electrospinning and types of collectors. Working parameters using electrospinning: solvent, needle, voltage, flow rate, needle-to-collector distance, rotational speed of collector. Frequent problems and technical solutions (e.g., bead formation in fibers; fiber formation in nanoparticles).
10. Bioceramics: General definitions of Ceramics, Glasses & Glass Ceramics; types of Bioceramics (Bioinert, Bioactive, Bioresorbable); Classifications of Bioceramics according to tissue attachment (dense nearly-inert, microporous nearly-inert, surface reactive, resorbable). Characteristics & Processing: Thermal equilibrium diagram for network forming oxide (SiO2) and arbitrary network modifier oxide (MO); plasma sprying, liquid-phase and solid-state sintering; mechanical properties. Bioceramics in medical devices: Dense nearly-inert ceramics (alumina and zirconia in orthopedics and dentistry, tribological properties); Porous ceramics (pore size and interconnectivity); Bioactive glasses & glass ceramics (biologically-active carbonated layer, bioactive bone-bonding boundary, bioactivity reaction stages); Bioresorbable Calcium Phosphate Ceramics (bone mineral matrix, hydroxyilapatite, tricalcium phosphates, degradation and mechanical behaviors).
11. Biomaterials for skin. Connective Tissue. Ground substance: amorphous substance (glycosaminoglycans, glycoproteins, proteoglycans) & fibrillar component (collagen, elastic and reticular fibers), cells of connective tissue (resident and circulating), types of connective tissues, basic histochemical staining. Epithelia: basal membrane, classification of covering epithelia according to cell shape and layer number, epidermis. Skin: tissue structure, wound and wound healing process; Skin models in vitro (cell cultures, skin equivalents) and in vivo (immunedeficient mice, diabete mice, rabbit, pig), advantages & shortcomings. Bioactive materials in skin wound healing and wound dressing (PLGA, PEG-DL-lactide copolymer, collagen, hyaluronan, lipid nanoparticles) for growth factor delivery (VEGF, PDGF, EGF, bFGF. IGF, TGF-β). New trends using oceanic biomaterials (salmon collagen, alginates, chitin/chitosan, fucoidan, carragenan, ulvan), acellular skin substitutes and stem cells. (SERENA DANTI)
12. Biomaterials for cartilage. Types of cartilages: hyalin, elastic and fibrous. Cartilage composition: connection of collagen type 2 fibrils with amorphous substance. Histologic description of cartilages. Cartilage cells. Perichondrium. Articular cartilage: Mechanical properties, different layers, pathologies (focal defect, degeneration), treatments (microfracture, mosaicoplasty, knee prosthesis, autologous chondrocyte transplantation, mesenchymal stem cell therapies) and limits. 3D scaffolds for articular cartilage (porosity - mesh size - dynamic stifness), scaffolds for osteochondral defects, pore interconnectivity, effect of scaffold architecture, chemistry and fabrication. Fibrocartilage: Intervertebral disc and meniscus morphology, pathology (degeneration, herniation) and treatments. Elastic cartilage: auricle and epiglottis, morphology, pathologies (anotia, microtia, autoimmune diseases). Hydrogels, biodegradable and biostable polymers for cartilage. 3D models of chondroscarcoma.
13. Biomaterials for bone. Bone tissue (compact, spongy), bone types (long, short, flat, odd), composition (mineral and organic matrix), lamellar structure (osteon, Harves and Volkmann channels, osteocyte) and periostium, osteogenic lineage and turnover, mechanosensing, osteoclasts and bone remodeling, bone homeostasis and vitamin D. Viscoelestic properties, mechanical properties of collagen fibers, compact and spongy bone (function of porosity), Young's modulus in different bone types. Pathologies and bone defects (tumor resection, mandibular reconstruction, cranial defects, osteoporosis, non-unions). Biomaterials: bone grafting, bioresorbable polymers (PLA, TCP, composites, fibrin gels, trimethylene carbonate and polydioxanone) for bulk devices (cages and screws) and tissue engineering in limb, spine and craniofacial bone defects. Vascularization issues.
14. Biomaterials for tendons/ligaments (T/L). Mechaniical properties (resilience, Young's modulus) and hierarchical structure from the triple helical collagen molecule to the tissues, T/L composition and cells (tenocytes, ligament fibroblasts). Ligaments: types and function: anterior cruciate ligament (ACL), medial collateral ligament (MCL). T/L injuries and burden. Fluoropolymers (partially fluorinated and perfluorinated) and their mechanical properties: PVDF, piezoelectricity and beta phase; PTFE, ePTFE (Teflon) and Goretex, porosity. Carbon fibers. Biotextiles (wovens, knits, braids and nonwovens). Synthetic biomaterials for T/L replacement (Gore-Tex, PEEK and carbon fibers, Dacron). Biomaterials for T/L tissue engineering: requirements and types: grafts, biological (silk fibroin), synthetic (polyhydroxyesters, PHBHHx, composites). Biomaterials for T/L transitional regions (muscle-tendon and ligament-bone junctions).
15. Biomaterials for ear (sensory organ case study). Ear anatomy: outer (pinna, auditory canal), middle (eardrum, ossicles) and inner (vestibular apparatus and cochlea) compartments. Ear physiology: conductive and sensoryneural sound transmission. Hints on vestibular organ and balance. Cochlear organ: ducts, fluids (perilymph, endoplymph), organ of Corti, hair cells (inner, outer), sensory neuron synapse, mechano-electrical transduction. Ear pathologies. Biomaterials for auditory canal and auricle. Middle ear biocompatibility & biomaterials: tympanic membrane replacements (grafts, biological materials/growth factors) and new approaches via additive manufacturing/electrospinning (PEOT/PBT) to induce stem cell alignment; Prostheses for ossiculoplasty (cartilage, porous plastics, bioactive ceramics, titanium, hydroxyapatite) and new approaches via tissue engineering and CAD-CAM techniques. Cochlear implant & new approach via piezoelectric biomaterials (ceramic/PVDF).
16. Biomaterials for muscles: skeletal, smooth, cardiac. Biomechanical properties (stiffness) of muscles. Skeletal muscle: collagen ECM (fascia, epimysium, perimysium, endomysium), hierarchical tissue organization (myofibrils up to muscular fiber, myoblasts), functional unit (sarcomere), contractile proteins (actin and myosin, thin and thick filaments), regulatory proteins, dystrophin, sarcoplasmatic reticulum, contraction mechanisms (sarcomere bands, ATP-ADP cycle and Ca++); skeletal muscle regeneration and repair; pathology: hereditary (muscle dystrophies) and acquired (trauma, tumor resection) diseases; in vitro and vivo regenerative medicine strategies; synthetic, natural, hybrid and hydrogel biomaterials, topographical and electromechanical cues. Smooth muscles: localizations, fibrocells and contraction proteins; biomaterials for vascular grafts (Dacron) and porosity.
17. Biomaterials for heart: Myocardium, cardiomyocytes, myocardium infarct, synthetic and natural biomaterials, microparticles. case studies (2): in vitro and in vivo approaches. Biodegradable biomimetic bioartificial 3D scaffolds (PHBHV/gelatin, PLGA/gelatin, PDS/gellan) produced via soft lithography: characterization and differentiative effect of topography on mesenchymal stem cells. Functionalized cardiac PLGA/gelatin patch. Biomaterials to prevent left ventricular remodeling, molecular imprinting technique. Injectable systems for cardiac tissue engineering and drug delivery in situ: Hydrophilic-hydrophobic bloc copolymers (mPEG-b-PCL/Gelatin) to control gelation temperature, shear-thinning behavior. Meso/nanoscale biomaterials with specific functions for acquired and hereditary pathologies. Synthetic, natural and bioartificial polymers, fabrication techniques, characterization (physico-chemical, mechanical, morphological, biological and functional). Olinucleotide-targeting nanospheres and nanocapsules for tumors. Smart membranes for neurodegenerative diseases, selectivity.
18. Biomaterial and device sterilization: by radiation (gamma, beta, electron beam and X-rays) vapor chemical (ethylene oxide), moist heat, liquid chemical, plasma, supercritical CO2; Mechanisms of microbial kill; Materials compatibility (effects on polymers chemistry, degradation and mechanical properties). Commercialization of biomaterials: market considerations on the biomedical industry; Idea-to-market; Intellectual property; Cost issues. Regulatory aspects: product validation by National Regulatory Institutions; Biocompatibility validation (ISO 10993; ISO 10993-5 cytotoxicity tests); CE mark; Clinical trials (randomized versus prospective observational); Ethical aspects (Declaration of Helsinki, GLP, GMP, GCP); Medical device and advanced therapy medicinal product. Implant failure and risk assessment.
19. Drug Delivery Systems (DDS): Introduction (definition of DD, traditional DDS). Principles, origins, evolution and advantages of Controlled Drug Delivery Systems (CDDS): History of CDDS, categorizing of DDS by the size: Macroscale DDS (“zero order” constant delivery rate DDS); Macroscale and microscale DDS (site-specific, sustained delivery rate DDS); Nanoscale DDS (targeted DDS). Nanoscale DDS (targeted DDS): Passive and active targeting. Injected depot DDS: Microparticle depots (microspheres), phase-separating depot systems. Implants and inserts: Non-degradable and biodegradable systems. Case study: PCL fibers containing drug-loaded gelatin nanoparticles.
20. 3R principles for alternative testing of biomaterials: replacement, reduction and refinement.

• Text book (suggested):

TITLE: Biomaterials Science: An Introduction to Materials in Medicine (Third Edition)

EDITOR: Buddy D. Ratner, Allan S. Hoffman, Frederick J. Schoen and Jack E. Lemons

ISBN: 978-0-12-374626-9

• Notes taken in class
• Slides give from the teacher after each class.

Contact the teacher for the didactical material and course information.

• The exam is made up of ongoing written assignments and one final oral test on a pre-selected topic among the organ applications. If a student does not provide assignments during the course, the oral test will cover all the program.
• The written assignments consist of: individual and gruop homework on specific case studies with written report or slide presentation.
• The written test will be passed if the student demonstrate in-depth knowledge, capability of summarizing, representing and discussing the findings.
• The oral test consists of an interview between the candidate and the lecturer on a topic selected by the student at the end of the course. It could be requested to also solve written problems/exercises in front of the lecturer. 
• The oral test will be passed if the student has demonstrated sufficient in-dept knowledge, has reached sufficient skills and behaviors on the selected topic.

This course of Biomaterials is designed to provide a general understanding of the multidisciplinary field of biomaterials, and to give a key focus on new products arising from nanotechnology. Specifically, it aims at developing in the attendants all the necessary skills as well as the fundamental theoretical and technical competences with the ultimate goal to have graduated students who can successfully interface with the multidisciplinary scenario of biomaterials-related products and technologies, both in industrial and research environments. The current and innovative applications of biomaterials will be evaluated to highlight the connections existing between material properties, function, biological responses and clinical applications. Due to the multidisciplinary nature of this topic, both teamwork and self-learning will be stimulated.