BIOMATERIALS & BIOCERAMICS |PROFILE · 2020. 6. 23. · All of these implants are made of...

The antimicrobial resistance crisis stopping

mission impossible

Modern medicine without new antibiotics and alternativeantimicrobial strategies would be an impossible mission

saved countless patients lives However it has alsobeen a constant head-to-head race betweenbacterial resistance development and thedevelopment of new drugs1

From the 1960s to the late 1980s the arsenal ofeffective antibiotics was filled by the work of manypharmaceutical companies In particular this led tothe extraordinary success of medicine and many ofits therapies especially surgical and interventionaltherapies However antimicrobial resistance (AMR)is ancient and the resistome (a term for all of theantibiotic resistance genes and their precursors inboth pathogenic and non-pathogenic bacteria) is ahighly dynamic and steadily increasing challenge2

Therefore all of the modern societies should have

AT a time when the SARS-CoV-2 virusinfection is spreading worldwide someof us are beginning to realise what social

and economic consequences an infection diseasecan have At the same time this infectious organicstructure presents us with social and logisticalchallenges rather than medical-therapeutic onesAlmost all social elites seem to be repressing the factthat mankind is facing another very slowly arisingthreat ndash the antimicrobial resistance crisis

The development of bacterial resistance againstantibiotics is an evolutionary survival process ofbacteria During the late 1930s Chain and Floreyfrom Oxford University began to work on penicillin aspart of a comprehensive research programme onantibacterial substances Since then antibiotics have

192 | The Innovation Platform ISSUE 2 | wwwinnovationnewsnetworkcom

copy iStocknarvikk

BIOMATERIALS amp BIOCERAMICS |PROFILE

globally but some data from the US and EuropeanUnion have given us a rough impression of howsubstantial the socio-economic burden actually isEvery year in the US 99000 patients die based onantibiotic-resistant pathogen-associated hospital-acquired infections (HAIs) In 2006 50000 patientsdied due to two common HAIs (pneumonia andsepsis) and as a result the economic burden wasaround $8b3

Hundreds of thousands of people worldwide(approximately 33000 in the EU) die every year fromthe consequences of infections with resistantbacteria The United Nations warns that deaths willskyrocket if this is not acted on immediatelyAccording to this 10 million people could die from

known that a drop in antibiotic research or even anend would result in them potentially losing the race

One of the reasons contributing to the AMR crisis isthat for almost a decade many big pharmaceuticalcompanies such as Bristol-Myers Squibb andAbbott have withdrawn from any highly expensiveand non-economically reimbursed antibiotic researchand development However this is only one of thecausing factors ndash summarised in Table 1 above arethe different causes of these non-judiciousbehaviours that have led to the global resistome andAMR crisis

The AMR crisis in numbersIt is still a huge challenge to evaluate the exacteconomic impact of resistant bacterial infections

wwwinnovationnewsnetworkcom | The Innovation Platform ISSUE 2 | 193

1) Overpopulation enhanced globalmigration and global misuse ofantibiotics by laymen and professionals

2) Excessive use of antibiotics in animals(food pets aquatic)

3) Inadequate hygiene standards inhealth care agriculture food industriesand stock farming etc

4) Senseless cost reduction or ignoringnecessary investigations in health care(eg hospitals)

5) Increased number of class 3 medicaldevices - potential risk of foreignmaterial-associated infections

6) Grossly negligent not to continueresearch and development of new antibiotics

7) Lacking knowledge about AMRmechanisms particularly in context ofFBR-associated colonization biofilmformation and infection

8) Missing or delayed translation andimplementation of alternativecomplementary drug-free antimicrobial strategies

The causes of the fast increasing global resistome and the resulting AMR crisis

AMR Antimicrobial crisis particularly antibiotic crisisFBR Foreign body reaction

PROFILE | BIOMATERIALS amp BIOCERAMICS

biomaterials often avoiding the hostrsquos immunedefence or applied antibiotics if the patient issuffering from an infection6

The biofilm as essential survival strategyof bacteriaAfter implantation of a medical device (such as anorthopaedic endoprosthesis) a competition betweenbacterial colonisation and tissue integration takesplace to conquer the surface of the implant Thisphenomenon was first described by Gristina et al in19887 Since then numerous specialist articles onthis topic have been published89 To simplify mattersthe example of the endoprosthesis remains wherebythe basic mechanistic and pathophysiologicalprinciples can be applied to any invasive implantFig1 shows a late periprosthetic joint infection (PJI)of a male patient with increasing problems one yearafter a primary total hip arthroplasty on the left side6

As soon as bacteria come into contact with suchimplant surfaces they adhere and colonise Duringthe first 48 hours the biofilm is in its juvenile stadiumand a few antibiotic strategies are still workingHowever once the biofilm has matured thesereserve antibiotic strategies will no longer work andthe last resort will be removing the implant

resistant bacteria every year by 2050 more thancancer today4

The consequences of the AMR crisis formodern medicineAll achievements of modern medicine are onlypossible through the application of medical devices(MD) This is especially true for class three invasivemedical devices according to the European Unionrsquosmedical device regulations (MDR) Annually around180000 pacemakers 260000 cardiovascular stents200000 hernia meshes 365000 hip and kneeendoprostheses are implanted into patients inGermany Furthermore millions of central venouscatheters ports urinary catheters and wounddressings for example are used invasively5

All of these implants are made of biomaterials withmedical grade approval Amongst them are differentclasses of materials such as metal alloys ceramicsand polymers Although these biomaterials aremainly described as lsquoinertrsquo (they do not harm thehostrsquos biology) or bio-active to support the hostrsquosbiology in different ways they still remain as foreignmaterials These foreign materials possess thedisadvantage that bacteria and commensals of thehost and pathogens interact with these biomaterialsin a severely dangerous manner Bacteria can formbiofilms on the outer and inner surfaces of such


Fig 1 Late periprosthetic joint infection (PJI) of a male patient with increasing problems one year after a primary total hip arthroplastyon the left side a) X-ray image showing the left hip region with the implanted total hip endoprosthesis composed of acetabular cupfixed into the socket of the hip bone by two pins and three screws femoral head made of ceramic and an intramedullary uncementedpress-fit stem The surface of the femoral stem is based on hydroxyapatite-coated titanium dioxide b) Enlarged section of the x-rayimage showing the interface between cortical bone and femoral stem surface The black arrows are indicating a radiolucent line atthe interface of the femoral component as a sign of osteolysis a typical radiological sign of loosening of the femoral stem c) Three-phase bone scintigraphy demonstrates the pathological uptake around the total hip replacement (THR) in the additional blood poolimage as positive sign of infection and septic loosening d) Scheme of the femoral stem ndash bone interface with the bone resorptionzones () showing the typical arrangement of osteocytes in cortical bone and activated osteoclasts responsible for the bone resorptionMicrobiological analysis of staphylococcus epidermidis confirmed the osteoclast activation and thus the PJI e) Schemedemonstrating the initial step and subsequent sequences of biofilm formation its maturation and the circulus vitiosus of biofilm-associated implant infections Reproduced and adapted with kind permission from Ayesha Idrees and PAGEPress6


Dr Jochen Salber (PhD MD)Senior Physician SurgeryHead of the Department of Experimental SurgeryDepartment of SurgeryUniversity Medical CentreKnappschaftskrankenhaus Bochum Hospital of the RUHR-University Bochum

+49 234 32 21819

jochensalberrubdewwwkk-bochumdewwwresearchgatenetlabJochen-Salber-Lab

References1 Ventola CL 2015 The Antibiotic Resistance Crisis Part 1 Causes

and Threats PampT 201540(4)277-283

2 Wright GD 2007 The antibiotic resistome the nexus of chemical andgenetic diversity Nature Reviews Microbiology 20075(3)175ndash186

3 Baloch Z et al 2018 Antibiotic resistance a rundown of a globalcrisis Infect Drug Resist 2018111645-1658

4 Baars CH and Lambrecht O 2019 Development of Antibiotics - Adisaster with an announcement Available athttpswwwtagesschaudeinvestigativndrantibiotika-pharmakonzerne

5 SalberJ and Viebahn R 2017 Biocompatibility of antimicrobialpolymeric materials for medical applications - How much in vitro ismandatory how much is sufficient eCM Meeting Abstracts TERMISEU 2017 Collection 20159161

6 Idrees A et al 2018 Drug-free antibacterial polymers for biomedicalapplications Biomedical Science and Engineering ndash PAGEPress20182(1)1-12wwwpagepressorgtechnologyindexphpbsearticleview39

7 Gristina AG Naylor P and MyrvikQ 1988 Infections frombiomaterials and implants a race for the surface Med Prog Technol198814(3-4)205-24

8 Wagner C and Haumlnsch GM 2015 Pathophysiology of implant-associated infections From biofilm to osteolysis and septic looseningOrthopaumlde 201544967ndash973

9 Zimmerli W and Sendi P 2017 Orthopaedic biofilm infectionsAPMIS 2017125353ndash364

10 Ghosh C Sarkar P and Issa R et al 2019 Alternatives toConventional Antibiotics in the Era of Antimicrobial Resistance TrendsMicrobiol 201927(4)323-338

Is the development of novel antibioticsthe only solutionThe answer to this question is no not at allScientists are working globally on alternativestrategies to conventional antibiotics such asantibodies probiotics bacteriophages antimicrobialpeptides biofilm-preventing and disrupting enzymesand last but not least antimicrobial implant surfacemodifcations10 Nevertheless without effectiveantibiotics and alternative complementaryantimicrobial strategies the success of major surgeryand interventional therapies temporarily appliedmedical devices or implanted mid- and long-termdevices would be strongly compromised

Modern medicine would become a mission impossible


The author was supported by the HyMedPoly projectHyMedPoly received funding from European UnionrsquosHorizon 2020 research and innovation programmeunder the Marie Skłodowska -Curie grant agreementNo 643050

Scientists areworking globally on

alternativestrategies toconventional

antibiotics such asantibodiesprobiotics

bacteriophagesantimicrobial

peptides biofilm-preventing and

disrupting enzymesand last but not

least antimicrobialimplant surfacemodifcations



Spider silk-based biomaterials a new opportunity for product

development in many industriesscale-up production to industrial scale and developproducts for the market at attractive prices

The innovative technology developed in our grouptogether with the scaling and application expertise atAMSilk brought new products to the markets whichndash apart from the outstanding properties of thematerial ndash might pose a solution to one of the biggestchallenges of our time reducing the plastic wasteand environmental burden of common crude-oilderived products via sustainable and biodegradableperformance biogenic materials

Processing spider silk proteinsbiomimetic spider silk fibresThe biomaterials group at the University of Bayreuthprocesses recombinant spider silk proteins into ahuge variety of morphologies including particlesfoams films hydrogels and non-woven matsamongst others (see Fig 1 left) One of the mostimportant processing breakthroughs was the firstproduction of a man-made spider silk fibre with atoughness indistinguishable to that of the naturalblueprint2 Based on that groundbreaking spider silktechnology the commercial fibre Biosteelreg wasdeveloped by AMSilk GmbH (see Fig 1 right) whichis already available on the market in textile productssuch as watch straps In this article the focus willhowever be on the biomedical applications of spidersilk-based materials

Biomedical applications of spider silkdrug delivery systemsDrug delivery systems are one of the most intensivelyinvestigated biomedical applications of materialsmade from recombinant spider silk proteins3 Due tothe different possible morphologies spider silk-based materials can be used both as stationary andmobile drug delivery systems Particles and thin-walled capsules are well suited for the latter Upongenetic modification of the recombinant spider silkprotein cell targeting sequences can beimplemented to be exposed on the surface of thedelivery system enabling a celltissue specific drugdelivery In contrast hydrogels as well as film

The development of the large-scale biotechnological production ofspider silk proteins in the last two decades has enabled newbiomaterials applications

Spiders have evolved silks which uniquelycombine tensile strength and extensibilitymaking it the toughest natural fibre material on

Earth even surpassing man-made materials such aspolyamides polyaramids or other performancefibres In contrast to those plastic materials spidersilk is a green polymer consisting of almost 100proteins which are fully biodegradable Therefore thebenefits of spider silks are manifold To date amyriad of possible uses for spider silk have beenproposed from medical applications to theincorporation in textiles

Spider silk has been utilised by humankind formillennia and biomedical applications in particularhave always been a central focus Spider webs wereused in ancient times by the Greeks and Romans tostop wounds from bleeding and trials with spider silkfibres as sutures go back to the 18th century A majordrawback in the past however has been lowproducibility partly based on the cannibalism of mostspiders which makes the natural scale-up ofproduction using spiders unfeasible

A breakthrough was the establishment of a scalablebiotechnological process enabling the production ofrecombinant spider silk derived proteins by our groupin 20041 The biotech process enables for the firsttime the scale-up of the production of such proteinsat constant high quality and yield Four years afterpublishing the first patents and research papers thespin-off company AMSilk GmbH (MartinsriedGermany) was launched in 2008 with the aim to

Fig 1 Left Morphologies made of recombinant spider silk proteinswhich can be used as biomaterials Right Biosteelreg fibres


Thomas ScheibelHead of Biomaterials and Vice PresidentUniversity of Bayreuth

+49 921 556701

thomasscheibelbmuni-bayreuthdewwwfiberlabde

amino acids are non-toxic to the body and can beeasily removed Since biodegradation is slow themechanical properties of spider silk-based implantsare maintained for a period lasting from weeks tomonths which is advantageous in severalbiomedical applications

Spider silk-based materials are therefore very wellsuited for clinical applications as drug deliverysystems or implant coatings as already shown butalso as artificial grafts for ligaments nerve boneskin and muscle amongst others

The necessary next steps for their commercialisationare clinical trials to obtain regulatory approvalTherefore we have started selected preclinicalstudies in order to gain more insights into thebiological integration and the functionality of spidersilk-based materials within the human body and topave the way for future applications

References1 Huemmerich D Helsen CW Oschmann J Rudolph R

Scheibel T (2004) lsquoPrimary structure elements of dragline silks andtheir contribution to protein solubility and assemblyrsquo Biochemistry43 13604-13612

2 Heidebrecht A Eisoldt L Diehl J Schmidt A Geffers M LangG Scheibel T (2015) lsquoBiomimetic Fibres Made of RecombinantSpidroins with the Same Toughness as Natural Spider Silkrsquo AdvancedMaterials 27 2189ndash2194

3 Aigner TB DeSimone E Scheibel T (2018) lsquoBiomedicalapplications of recombinant silk-based materialsrsquo AdvancedMaterials 30 1704636

4 Zeplin PH Maksimovikj NC Jordan MC Nickel J Lang GLeimer AH Roumlmer L Scheibel T (2014) lsquoSpider silk coatings as abioshield to reduce periprosthetic fibrous capsule formationrsquo AdvFunct Mat 24 2658-2666

coatings have been successfully tested as stationarydrug depots from which controlled release of low aswell as high molecular weight drugs and biologicalscan be realised

Biomedical applications of spider silkimplant coatingsUpon implantation a common biomaterialrsquos surfacecauses distinct body responses triggered byadsorbed proteins followed by monocyte andormacrophage adhesion Depending on thebiomaterial severe side reactions such asinflammation or scar formation can be the resultSpider silk has been shown to be highly compatiblewith the human body ie no or only little immunereaction has so far been identified which lowers therisk of inflammation andor later allergic responsestowards spider silk-based materials The lack of animmune response towards several tested spider silkmaterials is not fully understood but it could beshown that spider silk materials such as coatings or3D-printed hydrogels prevent infestation ofpathogens such as bacteria and fungi

This lack of cell adhesiveness might be one reasonfor the lsquostealth modersquo of spider silk surfaces insidethe human body One can use this property to maskestablished products such as catheters or siliconebreast implants by coating them with spider silk (Fig2 left)4 The latter are currently in a clinical study toreach regulatory approval

Biomedical applications of spider silk biofabrication Biofabrication is an additive manufacturingtechnology allowing the combination of living cellswith biomaterials serving as bioinks (mainlyhydrogels) in order to generate hierarchical tissue-like structures It has been shown that spider silkhydrogels show several beneficial properties to beused as a bioink material namely cell compatibilityadjustable mechanical properties in the regime ofliving tissues shear thinning behaviour enablingdispense blotting (Fig 2 right) and a fastregeneration of its shape through biophysicalcrosslinking (which allows to omit additives such ascross-linkers or plasticisers otherwise oftennecessary for 3D printing) Currently severalapproaches focus on the regeneration of peripheralnerves or heart muscle tissue based on recombinantspider silk based bioinks and materials

Next steps towards spider silk-basedmaterials in biomedicineSpider silk has been shown to allow angiogenesiswithout triggering inflammation which is a benefit interms of wound healing Furthermore thebiodegradability of spider silk enables a spider silkscaffold to be replaced with a new body-madetissue while the byproducts of degradation namely


Fig 2 Left Implants coatings made of spider silk reduce the risk offibrosis Right Spider silk hydrogels are shear thinning and can be3D printed (dispense plotted) without the aid of any additives Scalebar 1cm



Biomaterials in the fightagainst COVID-19

With advances being made in areas such as vaccine developmentand imaging biomaterials are playing a key role in efforts to beatthe COVID-19 virus

role to play In the healthcare field biomaterials aredefined by the European Commission as lsquomaterialsthat are entities surfaces or constructs that interactwith specific biological systems Biomaterialsscience encompasses elements of medicine biologychemistry tissue engineering and materialssciencersquo1 The document adds lsquoIn the health fieldthey become a whole or part of a living structure orbiomedical device with the objective of performingaugmenting or replacing a natural function Theymay be non-interactive with their environment suchas is the case for a heart valve or possess a moreinteractive functionality such as drug-impregnatedstents that release pharmaceutical products or morerecently to facilitate the operation of biomedicaldevices (BD) and advanced therapy medicinalproducts (ATMP) over prolonged periods of timersquo

The fight against COVID-19 is being made on all fronts A pandemic and public healthemergency the virus has seen many countries

close their borders and require their citizens ndash exceptfor key workers ndash to remain at home and lsquosociallydistantrsquo from all but those with whom they liveThese measures are crucial as they will preventhealth services from being overwhelmed will allowindustry to supply the inordinate amounts of PPEmedical equipment such as ventilators and othernecessary items and will mean that scientists havea little more time to not only better understand thisnew disease but also develop new ways to combatit ndash with the golden chalice being the developmentof a vaccine

It is within this last element of the efforts being madeto tackle COVID-19 that biomaterials have a clear

BIOMATERIALS amp BIOCERAMICS


that are contributing ideas and technology to theCenters for Disease Control and Prevention to fightthe COVID-19 outbreak He has proposed thatnanoparticles of similar sizes to the virus could attachto SARS-CoV-2 disrupting their structure with acombination of infrared light treatment Thatstructural change would then halt the ability of thevirus to survive and reproduce in the body

In South Korea Seasun Biomaterials an in vitrodiagnostic company that develops moleculardiagnostic platforms of infection diseases cancer aswell as genetic and epigenetic disorders hasannounced that it is to release its second COVID-19assay lsquoAQ-TOP COVID-19 Rapid Detection Kit justafter the completion of FDA EUA (April-27) of their U-TOP COVID-19 Real-Time Detection Kit The companysays that lsquoanalytical speed sensitivity and specificityof the conventional molecular methods were enhancedwith AQ-TOP technology through the combination ofisothermal amplification and PNA (Peptide NucleicAcid) detection probe which has high accurate bindingefficiency to the target nucleic acidrsquo They are set todistribute the kit around the world including Europeand the Middle Eastern countries

Europe and COVID-19In Europe the Commission has recently announcedthat following the publication of a euro10m call inJanuary it has secured an additional euro375m forurgently needed research on COVID-19 vaccinedevelopment treatment and diagnostics This actionis part of the co-ordinated EU response to the publichealth threat of COVID-19

The Commission says lsquoWith the additional amountfrom the Horizon 2020 programme the Commissionis scaling up the emergency call launched in Januaryto fight the COVID-19 outbreak to euro475m Thisallowed to select 17 projects involving 136 researchteams from across the EU and beyond which willstart working on developing vaccines newtreatments diagnostic tests and medical systemsaimed at preventing the spread of the CoronavirusrsquoGiven the above-mentioned advances taking placein the USA and South Korea there is certainly roomhere for the European biomaterials community tomake a significant contribution

Medical devicesAs quoted above biomaterials have applications infacilitating lsquothe operation of biomedical devices (BD)and advanced therapy medicinal products (ATMP)over prolonged periods of timersquo Indeed as FergalDonnelly from the European Commission DirectorateGeneral for Research and Innovation wrote in 2015lsquobiomaterials for health will become a major focus ofEuropean research efforts in the coming years andas part of the Horizon 2020 Framework Programmefor Research and Innovation They will findapplications particularly as integral parts ofAdvanced Therapy Medicinal Products (ATMPs) orindeed as complete or parts of Medical Devices The

Biomaterials researchThere are numerous examples of new researchmaking headway against COVID-19 on the Societyfor Biomaterialsrsquo website2 For example Fellows fromthe American Institute for Medical and BiologicalEngineering (AIMBE) have been deeply involved withthe wider medical and biological engineeringcommunity in responding to the COVID-19 in severaldifferent initiatives For instance Dr Maryellen Gigerhas been involved in a new effort to develop new AItools that uses images from chest X-rays andthoracic CT scans (which are potential exams forpatients due to the fact that severe cases of COVID-19 most often present as a respiratory illnesstriggering severe pneumonia) to diagnose monitorand help plan treatment for COVID-19 patients

Giger said ldquoWersquore taking our AI developmentknowledge that wersquove learned from analysing otherlung diseases and using it here In doing so we willconduct transfer learning and get away with a lotfewer cases as we combine medical imagingintelligence with machine intelligencerdquo

Elsewhere researchers at the University of SouthernCalifornia are working to develop and evaluate inpreclinical studies a new vaccine based on mRNAagainst SARS-CoV2 capable of inducing long-termimmune responses against the virus The team fromseveral laboratories at the university aim to producea synthetic vehicle based on innocuous biomaterialscapable of transporting the mRNA into the targetcells and enabling the production of the antigen inthe human body

Meanwhile Researchers at Northwestern Universityand Shirley Ryan AbilityLab in Chicago havedeveloped a novel wearable device about the size ofa postage stamp and are creating a set of dataalgorithms specifically tailored to catch early signs andsymptoms associated with COVID-19 and to monitorpatients as the illness progresses Capable of beingworn 247 the device produces continuous streamsof data and uses artificial intelligence to uncoversubtle but potentially life-saving insights Filling a vitaldata gap it continuously measures and interpretscoughing and respiratory activity in ways that areimpossible with traditional monitoring systems

Northwestern Engineeringrsquos John A Rogers who ledthe technology development said ldquoThe most recentstudies published in the Journal of the AmericanMedical Association suggest that the earliest signsof a COVID-19 infection are fever coughing anddifficulty in breathing Our device sits at the perfectlocation on the body mdash the suprasternal notch mdash tomeasure respiratory rate sounds and activitybecause thatrsquos where airflow occurs near the surfaceof the skinrdquo

Also in the USA Northeastern chemical engineeringprofessor Thomas Webster who specialises indeveloping nano-scale medicine and technology totreat diseases is part of a contingency of scientists



delaying the entry into application of new EU ruleson medical devices so we can have our medicalindustries pouring all their energy into what we needthem to be doing helping fight the pandemic Thisshows once again that the European Union is leavingno stone unturned in our support to national publichealth systems in their hour of needrdquo

Stella Kyriakides Commissioner for Health and FoodSafety added ldquoOur priority is to support MemberStates to address the coronavirus crisis and protectpublic health as powerfully as possible ndash by all meansnecessary Any potential market disruptionsregarding the availability of safe and essentialmedical devices must and will be avoided Todaysdecision is a necessary measure in these veryexceptional timesrdquo

The delay is also being applied to the Directive onactive implantable medical devices and the Directiveon medical devices but not to the In VitroDiagnostics Medical Devices Regulation whichbecomes applicable from 26 May 2022

Policy and research are thus two key pillars to theapproach now being taken across the world tocombat COVID-19 and biomaterials and associatedRampD is central to this The work being done aroundthe world on areas as diverse as imaging and vaccinedevelopment and the funding being made availableto undertake these efforts will continue to shape theresponse to the virus and hopefully will result in itbeing beaten

References1 BIOMATERIALS FOR HEALTH ndash A Strategic Roadmap for Research

and Innovation HORIZON 2020 (2010)

2 httpsbiomaterialsorg

relevant regulations that govern the marketing ofthese entities must be taken into consideration whenplanning research and development and variousincentives and assistance in that regard are availablefrom regulatorsrsquo

The main regulation important in this context is theMedical Devices Regulation According to theCommission lsquoFrom contact lenses and stickingplasters to pacemakers and X-ray scanners medicaldevices and in vitro diagnostic medical devices areessential to our health and quality of life as well as tothe European economyhellip To reflect progress over thelast 20 years the EU has therefore revised the legalframework Two new regulations ndash one on medicaldevices and the other on in vitro diagnostic medicaldevices ndash were adopted by the Council and theParliament and entered into force in May 2017rsquo withthe regulation on medical devices due to enter intoforce on 26 May 2021 following a transitional period

However on 3 April the Commission announced thatit had decided to postpone the date of application ofthe Medical Devices Regulation by a year in order lsquotoallow Member States health institutions andeconomic operators to prioritise the fight against thecoronavirus pandemic This decision takes intoaccount the unprecedented challenges of thecoronavirus pandemic and the need for an increasedavailability of vitally important medical devices acrossthe EU whilst continuing to ensure patient health andsafety until the new legislation becomes applicablersquo

Vice-President for Promoting our European Way ofLife Margaritis Schinas said ldquoShortages or delaysin getting key medical devices certified and on themarket are not an option right now The Commissionis therefore taking a pragmatic approach and



Mother Naturersquos bioscaffoldto restore health

characteristic rapidly lost following birth This fact isevidence for the genetically endowed potential forregeneration but the signals required to activate andrealise this potential in adults are unknown

Why did the evolution of Homo sapiensinclude the loss of regenerativecapability and replacement by scartissue formation The most common answer to this question is thatthere was an evolutionary survival advantage for this

Next generation extracellular matrix biomaterials promote healing ndashIs human tissue regeneration within reach

Unlike less-developed species such as theaxolotl and zebra fish the adult human haslimited ability to regenerate tissue following

injury1 2 Select tissues such as the liver bonemarrow and the inner lining of the intestinal tractretain regenerative potential in humans but mostother tissues respond to injury (heal) via well theunderstood processes of hemostasis inflammationand deposition of scar tissue Of note the developinghuman foetus and neonate have a more robust abilityto regenerate tissueorgans than adults a healing

Fig 1 Transmission electron microscopy of MBV (100000 X magnification)


contribute to regeneration may be a contributingfactor and could in part explain the inverserelationship between immune competence androbust regeneration4

While the addition of a highly specialised adaptiveimmune system brings improved host defenceagainst pathogens like viruses bacteria etc somespeculate that this defence function may come witha trade-off of full regenerative potential In foetaldevelopment for example the balance betweenimmune competence and regeneration favorsregeneration a function largely lost in later life Ofnote this trade-off may provide for greater protectionalso against cancer development and metastasiswhich involves many of the same mechanisms asimmune trafficking required for robust regeneration

Therapeutic approaches to stimulate regenerationshould be cognisant of these trade-offs nonethelessimportant clues continue to be unveiled as ourunderstanding of concomitant development ofspecialized immune function and regenerativecapacity expands

Regenerative Signals within ECMIt is recognised that molecular signals originating inthe extracellular matrix (ECM) can modulate theseemingly mutually exclusive processes of immunityand tissue regeneration although the specificbioactive molecules have yet to be identified

The ECM is a rich source of signalling molecules forboth the resident cells and cells that transit throughthe ECM in all tissues These signals maintain a cell-friendly homeostatic microenvironment during statesof health and mitigate the proinflammatory responseand facilitate functional tissue reconstructionfollowing injury Isolation of the ECM from tissuessuch as dermis small intestine and urinary bladderamong others by removal of cells (decellularisation)allows for the creation of ECM-based biomaterialsSuch ECM-based materials are currently available assurgical meshes for ventral hernia repairmusculotendinous repair5-9 and dura materreplacement10 11 among other therapeuticapplications12-15 and as powders for topical woundcare16 17 These embedded signalling molecules arereleased during the process of ECM degradation invivo These signalling molecules favourably modulatethe innate immune response and provide amicroenvironment that influences cellulardifferentiation and spatial organisation18-22 Theclinical outcome includes partial restoration of siteappropriate normal tissue structure and function

trade off Risk of exsanguination and infectionfollowing traumatic injury drove the selection of aswift albeit imperfect healing process (iehaemostasis and scarring) over regeneration Thisexchange for survival comes with the cost ofincreased morbidity and decreased tissuefunctionality both of which are dependent upon thelocation and extent of injury A clinical example of thepros and cons of this evolutionary selection can befound in patients with traumatic injury in whichmassive amounts of extremity muscle tissue aredestroyed or lost (ie volumetric muscle loss) Theability to halt the haemorrhage by blood clotformation and overcome associated wound infectionavoids loss of life but the resulting replacement ofskeletal muscle by scar tissue markedly compromisessubsequent limb function

Are there therapeutic strategies that compensate for loss of regenerative abilityMany strategies for functional tissue replacementexist including cell-based therapies 3-D printingand tissueorgan culture however successful clinicaltranslation of these approaches has been verylimited An alternative strategy involves theresurrection or reactivation of at least some of theinherent regenerative capacity that exists in thehuman genome Can therapeutic approaches bedeveloped that both retain immediate life-preservingprocesses and simultaneously activate themolecular signals required to promote and facilitatethe otherwise silent genetically-driven pathways oftissue regeneration

To answer these questions we turn to the immunesystem Once thought to have the singular functionof protection against pathogens and tissue injurystudies within the past two decades have identifiedthe critical role the immune system plays in normaltissue development and tissue regenerationImmune system function in higher mammalsincluding both the innate and adaptive arms istightly linked to wound healing and inherentregenerative potential and must be spatially andtemporally regulated for any true regeneration tooccur Without such regulation scarring resultslimiting regenerative capacity

There is some evidence that evolution of the adaptiveimmune system is inversely correlated withregenerative capacity3 Though the true link betweenthese two evolved and devolved traits is not wellunderstood the shared trafficking mechanismsbetween immune cells and stemprogenitor cells that



The next generation of ECM-based therapeutics willundoubtedly involve the identification and use ofvarious formulations of ECM such as hydrogels thatcan be injected by minimally invasive methods andthe use of specific components of the ECM that areshown to possess immunomodulatory properties Anexample of the latter is the recent identification ofmatrix bound nanovesiclersquos (MBV)30 These nano-sized lipid bound vesicles are firmly embeddedwithin the structural components of the ECM and area distinct subset of extracellular vesicles from themore commonly described exosomes found in bodyfluids31 MBV have potent immunomodulatoryproperties32 and are only released from their ECMmicroenvironment when the matrix is degraded asoccurs following tissue injury or during thedegradation of an ECM biomaterial The size andabundance of MBV provide great flexibility fortherapeutic delivery and expansion of the use ofnaturally occurring signalling molecules to restorehealthy tissue

Advancements in surgical technique 3-D printing oftissues and organs bioreactor technology stem cellbiology and related disciplines will clearly have apositive impact upon the clinical translation ofregenerative medicine It is just as evident that ourunderstanding and ability to influence naturallyoccurring pathways of tissue development andregeneration through the use of ECM-based signalsand related technologies will have a significantimpact upon future therapeutic approaches

Intellectual property related to the hydrogel form of extracellular matrixand matrix bound nanovesicles has been licensed to ECM TherapeuticsInc a company in which SFB and JLD have a vested interest and holdofficer positions

References1 AW Seifert K Muneoka lsquoThe blastema and epimorphic regeneration

in mammalsrsquo Dev Biol 433(2) (2018) 190-199

2 SA Eming P Martin M Tomic-Canic lsquoWound repair andregeneration mechanisms signaling and translationrsquo Sci Transl Med

6(265) (2014) 265sr6

3 JW Godwin AR Pinto NA Rosenthal lsquoChasing the recipe for a pro-regenerative immune systemrsquo Semin Cell Dev Biol 61 (2017) 71-79

4 J Wang H Knaut lsquoChemokine signaling in development anddiseasersquo Development 141(22) (2014) 4199-205

5 NA Kissane KM Itani lsquoA decade of ventral incisional hernia repairswith biologic acellular dermal matrix what have we learnedrsquo Plast

Reconstr Surg 130(5 Suppl 2) (2012) 194S-202S

6 S Badylak S Arnoczky P Plouhar R Haut V Mendenhall R ClarkeC Horvath lsquoNaturally occurring extracellular matrix as a scaffold formusculoskeletal repairrsquo Clin Orthop Relat Res (367 Suppl) (1999)S333-43

7 NJ Turner JS Badylak DJ Weber SF Badylak lsquoBiologic scaffoldremodeling in a dog model of complex musculoskeletal injuryrsquo J Surg

Res 176(2) (2012) 490-502

8 NJ Turner SF Badylak lsquoBiologic scaffolds for musculotendinous

Using the principles of Mother Nature torestore healthy tissueThe concept of the microenvironment and specificallythe ECM regulating cell and tissue morphogenesis isnot new Bissell23-25 and Sonnenschein26 have studiedthese concepts primarily in the context of cancerfocused upon the direct cell-matrix bi-directionalcrosstalk without mention of the indirect and paracrineinfluence of the immune system Sonnenschein hasreferred to the temporal and spatial effects of themicroenvironmnet upon cell behaviour as the tissueorganisation field theoryrsquo (TOFT)27

One example of a clinical application in which theECM when used as a biomaterial can redirectdysregulated cell-signalling mechanisms involves itstherapeutic use for the treatment of oesophagealadenocarcinoma15 Following full circumferentialmucosal resection of the cancerous mucosa anECM bioscaffold was implanted in five patientsPatients achieved complete regeneration of a near-normal oesophageal mucosa and remained cancerfree after a follow-up of more than five years The useof this acellular regenerative medicine approachavoided the highly morbid procedure ofesophagectomy stricture (ie scar tissue) formationand cancer progression The restoration of normal ornear normal tissue is an example of modulating thedefault tissue repair pathways toward activation ofendogenous constructive and functional repairpathways by utilisation of Mother Naturersquos signalsembedded within the ECM This approach is a viablealternative to tissue engineeringregenerativemedicine approaches that involve cell-based therapyor exogenous tissueorgan creation with subsequentsurgical implantation

A second clinical example of using naturallyoccurring signals to promote functional tissuerestoration involves the use of ECM bioscaffolds forskeletal muscle repair 13 patients with volumetricmuscle loss had exhausted all attempts to replacemissing muscle tissue with conventional therapies14

Following implantation of a surgical meshcomposed of ECM the average patient showed a37 increase in strength 38 restoration ofmuscle mass and greater the 250 improvementin ability to perform muscle functional activities Thiscohort study followed extensive preclinical work inwhich ECM signalling molecules were shown tomitigate the proinflammatory immune response andpromote the proliferation and differentiation ofmuscle progenitor cells22 28 29



Professor Stephen F BadylakMcGowan Institute for RegenerativeMedicineUniversity of Pittsburgh

ECM Therapeutics118 Marshall DriveWarrendale PA 15086

+1 412 624-5308

badysxUPMCEDUTweet McGowanRMhttpsmirm-pittnetwwwecmtherapeuticscom

tissue repairrsquo Eur Cell Mater 25 (2013) 130-43

9 NJ Turner AJ Yates Jr DJ Weber IR Qureshi DB Stolz TWGilbert SF Badylak lsquoXenogeneic extracellular matrix as an inductivescaffold for regeneration of a functioning musculotendinous junctionrsquoTissue Eng Part A 16(11) (2010) 3309-17

10 MA Cobb SF Badylak W Janas FA Boop lsquoHistology after duralgrafting with small intestinal submucosarsquo Surg Neurol 46(4) (1996)389-93 discussion 393-4

11 MA Cobb SF Badylak W Janas A Simmons-Byrd FA BooplsquoPorcine small intestinal submucosa as a dural substitutersquo Surg

Neurol 51(1) (1999) 99-104

12 HE Mewhort JD Turnbull HC Meijndert JM Ngu PW FedaklsquoEpicardial infarct repair with basic fibroblast growth factor-enhancedCorMatrix-ECM biomaterial attenuates postischemic cardiacremodelingrsquo The Journal of thoracic and cardiovascular surgery 147(5)(2014) 1650-9

13 KA Derwin SF Badylak SP Steinmann JP Iannotti lsquoExtracellularmatrix scaffold devices for rotator cuff repairrsquo J Shoulder Elbow Surg

19(3) (2010) 467-76

14 J Dziki S Badylak M Yabroudi B Sicari F Ambrosio K StearnsN Turner A Wyse ML Boninger EHP Brown JP Rubin lsquoAnacellular biologic scaffold treatment for volumetric muscle lossresults of a 13-patient cohort studyrsquo NPJ Regen Med 1 (2016) 16008

15 SF Badylak T Hoppo A Nieponice TW Gilbert JM Davison BAJobe lsquoEsophageal preservation in five male patients after endoscopicinner-layer circumferential resection in the setting of superficialcancer a regenerative medicine approach with a biologic scaffoldrsquoTissue Eng Part A 17(11-12) (2011) 1643-50

16 CD Prevel BL Eppley DJ Summerlin R Sidner JR Jackson MMcCarty SF Badylak lsquoSmall intestinal submucosa utilization as awound dressing in full-thickness rodent woundsrsquo Ann Plast Surg 35(4)(1995) 381-8

17 NJ Turner SF Badylak lsquoThe Use of Biologic Scaffolds in theTreatment of Chronic Nonhealing Woundsrsquo Adv Wound Care (NewRochelle) 4(8) (2015) 490-500

18 EP Brennan J Reing D Chew JM Myers-Irvin EJ Young SFBadylak lsquoAntibacterial activity within degradation products ofbiological scaffolds composed of extracellular matrixrsquo Tissue Eng

12(10) (2006) 2949-55

19 EP Brennan XH Tang AM Stewart-Akers LJ Gudas SFBadylak lsquoChemoattractant activity of degradation products of fetaland adult skin extracellular matrix for keratinocyte progenitor cellsrsquo JTissue Eng Regen Med 2(8) (2008) 491-8

20 LT Saldin S Patel L Zhang L Huleihel GS Hussey DG NascariLM Quijano X Li D Raghu AK Bajwa NG Smith CC ChungAN Omstead JE Kosovec BA Jobe NJ Turner AH Zaidi SFBadylak lsquoExtracellular Matrix Degradation Products DownregulateNeoplastic Esophageal Cell Phenotypersquo Tissue Eng Part A 25(5-6)(2019) 487-498

21 S Tottey M Corselli EM Jeffries R Londono B Peault SFBadylak lsquoExtracellular matrix degradation products and low-oxygenconditions enhance the regenerative potential of perivascular stemcellsrsquo Tissue Eng Part A 17(1-2) (2011) 37-44

22 BM Sicari JL Dziki BF Siu CJ Medberry CL Dearth SFBadylak lsquoThe promotion of a constructive macrophage phenotype bysolubilized extracellular matrixrsquo Biomaterials 35(30) (2014) 8605-12

23 MJ Bissell MH Barcellos-Hoff lsquoThe influence of extracellular matrixon gene expression is structure the messagersquo J Cell Sci Suppl 8(1987) 327-43

24 CM Ghajar H Peinado H Mori IR Matei KJ Evason H BrazierD Almeida A Koller KA Hajjar DY Stainier EI Chen D LydenMJ Bissell lsquoThe perivascular niche regulates breast tumourdormancyrsquo Nat Cell Biol 15(7) (2013) 807-17


Co-authorJenna DzikiResearch Assistant ProfessorMcGowan Institute for Regenerative Medicine University of Pittsburgh

25 CD Roskelley MJ Bissell lsquoDynamic reciprocity revisited acontinuous bidirectional flow of information between cells and theextracellular matrix regulates mammary epithelial cell functionrsquoBiochem Cell Biol 73(7-8) (1995) 391-7

26 CM Markey MA Coombs C Sonnenschein AM SotolsquoMammalian development in a changing environment exposure toendocrine disruptors reveals the developmental plasticity of steroid-hormone target organsrsquo Evol Dev 5(1) (2003) 67-75

27 AM Soto C Sonnenschein lsquoEmergentism as a default cancer as aproblem of tissue organizationrsquo J Biosci 30(1) (2005) 103-18

28 JL Dziki RM Giglio BM Sicari DS Wang RM Gandhi RLondono CL Dearth SF Badylak lsquoThe Effect of MechanicalLoading Upon Extracellular Matrix Bioscaffold-Mediated SkeletalMuscle Remodellingrsquo Tissue Eng Part A (2017)

29 JL Dziki BM Sicari MT Wolf MC Cramer SF BadylaklsquoImmunomodulation and Mobilization of Progenitor Cells byExtracellular Matrix Bioscaffolds for Volumetric Muscle LossTreatmentrsquo Tissue Eng Part A (2016)

30 L Huleihel GS Hussey JD Naranjo L Zhang JL Dziki NJTurner DB Stolz SF Badylak lsquoMatrix-bound nanovesicles withinECM bioscaffoldsrsquo Sci Adv 2(6) (2016) e1600502

31 GS Hussey C Pineda Molina MC Cramer YY Tyurina VA TyurinYC Lee SO El-Mossier MH Murdock PS Timashev VE KaganSF Badylak lsquoLipidomics and RNA sequencing reveal a novelsubpopulation of nanovesicle within extracellular matrix biomaterialsrsquoSci Adv 6(12) (2020) eaay4361

32 GS Hussey JL Dziki YC Lee JG Bartolacci M Behun HRTurnquist SF Badylak lsquoMatrix bound nanovesicle-associated IL-33activates a pro-remodelling macrophage phenotype via a non-canonical ST2-independent pathwayrsquo J Immunol Regen Med 3(2019) 26-35



Advances in bioprinting

Furthermore only aqueous cell suspensions can beprinted to avoid print valve clogging

On the other hand micro-extrusion allows for theprinting of viscous cell solutions bioinks as strands togenerate different tissue layers In collaboration withregenHU ZHAW was producing a bioprinted full-thickness skin model supported by the Swiss fundingagency Innosuisse (Grant Nos 121482 amp 143311)The goal of the skin bioprinting project was to providethe cosmetic industry with advanced human skinmodels to address the hazardous potential of cosmeticingredients such as corrosion or irritation effects

For the bioprinting process a bioink was developedat ZHAW that was later commercialised by regenHUThe bioink consisted of gelatin and PEG Gelatin as aderivative of collagen I provided cell adhesion sitesand showed favourable printing properties at roomtemperature (RT) because of temperature-dependentpolymerisation PEG on the other hand served asspacer between the gelatin molecules In order torender the bioink stable at physiological conditions(37degC) the gelatin was methacrylated and wascombined with methacrylated PEG Polymermethacrylation allowed light-induced polymerisationwith the help of a photoinitiator The following protocolwas developed to produce full-thickness skin models bull The bioink without cells was printed in extrusion

mode and each layer was photo-polymerized before

bull Primary human dermal fibroblasts were printedwith inkjet mode on the polymerized bioink layer

These steps were alternated eight times to generatea dermal equivalent (see Fig 1) The dermalequivalent was incubated for up to several weeks tolet the tissue mature and afterwards the epidermiswas produced by placing primary humankeratinocytes on top of the dermal equivalent In thismanner we successfully printed a skin model2 Theapproach was further developed and implementedat a cosmetic company In another collaboration with

Biomaterials are key for the success of bioprinting

The artificial production of tissues has been adream for many scientists and clinicians fordecades In the early phases of tissue engineering

acellular scaffolds were implanted into the defectivetissue site of patients to be repopulated by body cellsto regenerate the defect Thus the name lsquotissueengineeringrsquo mainly referred to applications inregenerative medicine Although the expectations intissue engineering were rather high the progress inthis field was quite slow It was only with the adventof three-dimensional (3D) cell culture technologies thatthe field of tissue engineering received new impetus

In the first decade of the 21st century it becameevident that cells grown in 3D better represent humanphysiology than cells grown in standard monolayer 2Dcultures With this further development of 3D cellcultures the application range also broadened fromregenerative medicine to drug developmentsubstance testing and personalised medicine Inscaffold-based 3D cell cultures biomaterials (scaffolds)are used to provide a 3D environment for the cellsBiomaterials developed for 3D cell culture aresubdivided into synthetic or natural biomaterials basedon their origin Commonly used natural polymersinclude collagen I Matrigel fibrin alginate cellulosehyaluronic acid gelatine or mixtures thereof whereassynthetic polymers are based on poly(ethylene glycol)(PEG) polyurethane and poly(vinyl alcohol)

For printing purposes the rheological propertiesneed to be considered and adapted accordinglyCurrently many of these biopolymers are modified tomake them suitable for bioprinting Bioprinting ismainly based on three technologies bull Laser-assisted bioprinting

bull Inkjet-bioprinting and

bull (Micro-) extrusion-bioprinting1

Bioprinting is expected to revolutionise tissueengineering because it allows tissue generation in anadditive manner by the controlled deposition of cellsbiomaterials and bioactive molecules in 3D space

Bioprinting at ZHAWIn 2010 the ZHAW teamed up with the Swisscompany regenHU regenHU is a pioneer in providingbioprinting solutions for different applications intissue engineering The regenHU bioprinter installedat ZHAW laboratories was providing inkjet and micro-extrusion printheads Inkjet printing allows celldeposition in small droplets in an aqueous solutionThe advantage of inkjet printing is the high printingresolution of 20μm at the expense of printing speed

Fig 1 Bioprinted dermal equivalent in a well of a 24 well platedirectly after the printing process The cells are not visible The edgelength of the printed square is approximately 1cm


Dr Markus RimannHead of TEDDGroup Leader 3D Tissues and BiofabricationICBT Institute of Chemistry and BiotechnologyZHAW Zurich University of Applied Sciences

+41 (0)58 934 55 12

markusrimannzhawchwwwzhawchicbt3d-tissues-and-biofabrication

organs is the integration of blood supply Thus manyresearch groups are working on the integration of thevasculature in the bioprinted tissues with increasingsuccess It will therefore just be a matter of timebefore we will have fully vascularised tissuesorgans

On other the hand there are many applications in thefield of drug development where blood supply is notimportant due to the small tissue size with the benefitof being able to replace animal experiments which isbecoming increasingly demanded by society

Finally yet no less importantly let us keep in mindthat bioprinting is not the solution for every tissue-engineering problem It is just a way to assemblecells in vivo-like in 3D but without an additionalincubationmaturationdifferentiation step a tissuewill not be built

References1 Jos Malda et al lsquo25th Anniversary Article Engineering Hydrogels for

Biofabricationrsquo Advanced Materials 2013 DOI 101002adma201302042

2 Markus Rimann et al lsquoStandardized 3D Bioprinting of Soft TissueModels with Human Primary Cellsrsquo Journal of Laboratory Automation1ndash14 2015 DOI 1011772211068214567146

3 Sandra Laternser et al lsquoA Novel Microplate 3D Bioprinting Platformfor the Engineering of Muscle and Tendon Tissuesrsquo SLAS Technology1ndash15 2018 DOI 1011772472630318776594

the pharma industry we developed a muscle-tendontissue for drug development Innosuisse supportedthe project (Grant Nos 163131 amp 279011) Thebioink developed for the skin project served asmaterial for the bioprinted muscle tissues

As a prerequisite for the functional analysis of skeletalmuscle tissues a 24 well plate was developed toculture the tissues between two posts that wereplaced in each of the wells Primary human skeletalmuscle derived cells in combination with primarytenocytes (to represent tendon tissue) were printed toplace tenocytes around the posts and muscle cellsbetween the posts This printing pattern was reflectingthe in vivo-like tissue organisation while tendon isattached to the bone (posts) and muscle tissue isbetween the tendon tissue and between the posts

The main challenge of this project was the co-differentiation of the two cell types into the twocorresponding tissues after the printing processAfter the differentiation process into muscle fibresthe tissue was contracting after electrical stimulationproofing muscle functionality3

Later with an extended collaboration consortium wedeveloped a device that electrically stimulated andat the same time optically monitored muscle tissuecontraction through post bending underphysiological conditions In a proof-of-concept studyeffects of know compounds could be reproduced(publication in preparation)

The TEDD networkWhile bioprinting technology is developing very quicklythe development of suitable bioinks is lagging behindIn the beginning the idea was to develop a so-calledlsquouniversal bioinkrsquo to produce any kind of tissue Todayit has become clear that there is no such universalbiomaterial but that every tissue has its own cellmicroenvironment that needs to be reproduced to acertain extent In order to develop specific bioinksexperts from the clinics biology chemistry materialsciences and engineering need to join forces In 2010the ZHAW together with the company InSpherofounded the Competence Centre TEDD (TissueEngineering for Drug Development and SubstanceTesting TEDD) with the goal of further developing invitro 3D cell culture technologies and itsimplementation in different industries (pharmamedtech cosmetic) (see Fig 2)

It is a collaboration platform to bring together differentstakeholders from basic applied and clinical researchenabling technology providers and industry to developnew solutions in the field In 2017 the TEDD AnnualMeeting was fully dedicated to latest advancementsin bioprinting During the meeting new collaborationswere initiated to boost the bioprinting field

Conclusions and future directionsThe ultimate goal of bioprinting is to produce artificialorgans for organ transplantation eg liver kidney etcSo far only small tissues have been bioprinted Oneof the obstacles to generate larger tissues or even


Fig 2 TEDD is a collaborative platform and network dedicated tothe advancements of 3D cell culture technologies includingbioprinting and biomaterial development



Biomedical engineering ndashwho wants to live forever

COVID-19COVID-19 is a virus which is caused by severe acuterespiratory syndrome and is shown to displaysymptoms between six and 41 days with the mostcommon being 14 days The virus first broke out inWuhan China in December 2019 and spread acrossthe globe within weeks So much so that the WHOdeclared to be a Public Health Emergency ofInternational Concern on 30 January 2020

There has been worldwide concern that there is ashortage of available ventilators which are requiredto support patients with this lift threatening illnessFor many patients critically ill with COVID-19 aventilator could be a matter of life or death Themachine works to get oxygen to the lungs whilstremoving carbon dioxide which is essential forpatients who are too sick to breathe on their own

BME plays a huge part in manufacturing thesebreathing devices and ensuring they arecompatible Furthermore ventilators are verydifficult to manufacturer due to their uniquestructure and programming

ldquoThese are extremely sensitive machines with not onlya lot of hardware but also a lot of software If one ofthe components does not work correctly the wholemachine shuts down and cannot be used anymorerdquoexplained Jens Hallek CEO at Hamilton Medical

However both large and small companies are joiningforces in order to tackle the virus once and for allAccording to the Daily Mail a UK newspaper afamily run engineering company located in Wales aredeveloping a new ventilator to treat patients It issaid they are en route to producing 100 ventilatorsa day This engineering company CR Clarke ndash whichusually designs plastic fabrication equipment forindustry ndash was approached by Dr Rhys Thomas(NHS Senior) who was concerned at the lack ofintensive care unit ventilators

Weaknesses of BMEThe biomedical engineering profession and industrycontinues to receive a lot of praise for the advances

Amy Leary marketing manager at eBOMcom discusses the role of biomedical engineering particularly during the currentCOVID-19 pandemic

Biomedical engineering is a huge topicnowadays ndash especially with COVID-19circulating the globe Biomedical engineering

(often known as lsquomedical engineeringrsquo) is the termused for the combination of biology and engineeringor applying engineering materials to medicine andhealthcare BME (biomedical engineering) is veryimportant for the healthcare industry ndash fromadvancing medical treatments to monitoring acondition ndash without it the healthcare industry wouldbe very unreliable

HistoryBME was first introduced by Alfred E Mann aphysicist entrepreneur and philanthropist Since thenthe 1970s the sector has developed in leaps andbounds and the first dedicated institution was built in1998 at the University of Southern California USA

Especially during the last few years BME has beenextremely important for improving healthcare andmedical devices Most biomedical engineers areemployed for scientific research pharmaceuticalcompanies and manufacturing firms It was in 1993when five biomedical engineers in Edinburgh UKcreated the first functional bionic arm ndash also know asthe lsquoEdinburgh Modular Arm Systemrsquo This specificarm consisted of miniature motors microchips andgrips which allowed the artificial fingers to gripobjects along with a twistable wrist

Now bionic arms are so much more advanced andexpensive In todayrsquos era prosthetic arms are madefrom strong durable lightweight materials such ascarbon fibre and have a very different structureNowadays implants are placed in the sensorysystem to control nerve action rather than devicesattached to the body by straps or artificiallypowered said Jacky Finch a researcher in the KNHCentre for Biomedical Egyptology at the Universityof Manchester UK

As technology has developed so has biomedicalengineering In the last decade advanced electronicshave assisted us in accessing many of the necessaryscientific details


Amy LearyMarketing Manager eBOMcom

+44 (0) 1892 613400

amylearyebomcomTweet elecbomwwwebomcom

manufactures have joined forces in rapidly producingventilators Elsewhere a ventilator specialist isdrawing on manufacturing support from firmsincluding Formula 1 teams McLaren MercedesFord Siemens and Meggitt

Tesla are also contributing to tackle the virus Asstated in Forbes the coronavirus crisis has led ElonMusk to jump into the medical device industry withSpaceX fabricating components for Medtronic MDTventilators corporate donations of BiPAP breathingmachines that can be modified for use as non-invasive ventilators and promising to use a TeslaTSLA factory to produce ventilators Now Teslaengineers have designed a prototype ventilator thatuses parts adapted from electric vehicles

Biomedical engineers are in high demand in order tokeep on top of the safety trends which this virus iscausing globally As a result there is a very strongsense that this industry will continue to go fromstrength to strength

it makes and the problems it solves However thereis also some controversy when it comes to changingthe fate of someonersquos life by an unnatural source ndashsuch as ventilators bionic prosthetics etc Indeedsome people have questioned the morality of BMEbecause it is not lsquowhat was intendedrsquo and othershave even come to view BME as a form of mutilationof the existing species

In addition in some rare cases biomedicalengineering could potentially and albeitunintentionally harm humans For instance there isevidence to suggest that BME may cause thedevelopment of drug resistant pathogens

Strengths of BMEBut if course there are numerous benefits to BMEtoo In times like this with COVID-19 spreadingacross the globe we are fortunate that BME is soadvanced and successful Bioengineering has playeda vital role in ensuring that common diseases aredefeated Through genetic modification somediseases have been beaten while others have beenneutralised And it is thanks to BME that people areliving longer ndash as a result of the technology andmodifications it brings about Indeed scientists havebeen able to extend the life of some organisms by afew years

Market insightsAs you can image due to coronavirus the demandfor the most advanced biomedical engineering hasrocketed Many organisations such as car




Harvesting mammalian cellswith only one filter per batch

support for the filter cake consisting of cells andfilter aid As a result the filtration is much fasterand the filter media can be regenerated by beingback-flushed from the opposite side and

2) Cyclic Operation Since the filter media can beregenerated the filter can be operated in a cyclicmanner that is illustrated in Fig 1 (see above)

The working principle of a single filtration cycle isillustrated in Fig 1 The filter is filled throughconnector one and once filled the liquid pushesthrough the filter media into the vertical elements andexits the filter through connector two As the filtrationis carried out a cake forms on each element

When the cake has grown to a degree that causes asignificant drop in the flow rate it then proceeds tothe next step the heel volume (HV) filtration Air ispumped between the filter bag and the filterhousing squeezing all the remaining liquid out of thebag In the subsequent step the filter elements areback-flushed by pumping water for injection (WFI) orbuffer through connector two As a result the cakeis removed from the filter elements and the filtermedia is regenerated for the next cycle The filtercake accumulates as a slurry at the bottom of thebag and is discharged by opening the bottom pinchvalve Doing so regenerates the entire filter bag forthe next cycle

DrM from Switzerland manufactures innovative filters that can tacklelarge batch sizes and cell concentrations in the production of biologics

ASthe biologics industry is moving towardsmore diverse batch volumes and cellconcentrations that are cultivated in

single-use facilities there has been a demand forinnovative cell separation technologies Conventionaltechnologies such as depth and cross-flow filtershave limited flow rates extremely large footprintsand rely on high filter areas The latter causes a highamount of leachables and extractables isunsustainable and causes high investment andoperating costs1

The innovative CONTIBACreg SU filter developed byDrM Dr Mueller AG in Switzerland overcomes theselimitations by using a cyclic cake filtration methodThanks to the cake filtration this particular filter hasan unequalled speed without sacrificing filtratequality and the cyclic operation allows for filteringthe same batch volume with a smaller filter Thismeans that by using a smaller filter not only is it moresustainable but it also significantly reduces the riskof contamination

The working principleThe CONTIBACreg SU introduced in this study by DrMovercomes the limitations of current mammalian cellseparation technologies by using two novel concepts 1) Cake Filtration The filter media does not perform

the actual filtration but instead it acts as a

Fig 1 Filtration steps that comprise one complete cycle of the CONTIBACreg SU2


Tizian BucherHead of RampDDrM Dr Mueller AG

+41 44 921 21 21

mailboxdrmchwwwdrm-lifesciencecom

Therefore there was no sign of fouling or dip in theperformance something that cannot be achievedwith conventional filters Depth filters for instancecannot be back-flushed and even experience severefouling within a single filtration cycle Cross-flowfilters require high flow speeds and thereby inducecell damage which inevitably causes fouling Unlikein these two technologies the filter media in theCONTIBACreg SU does not perform the actualfiltration but instead acts as a cake support therebybeing less susceptible to fouling Moreover the pHreduction agglomerates impurities such as celldebris DNA and host cell proteins (HCP) andfacilitates their separation from the liquid3

The high performance of the CONTIBACreg SU doesnot come at the cost of filtrate quality The filterreduced the turbidity by 98-99 and the amount ofdeoxyribonucleic acid (DNA) content by up to 90The activity of lactate dehydrogenase (LDH) ameasure of the amount of cell damage only roughlydoubled which is an outstanding result compared tocompeting technologies3

ConclusionThe innovative filtration technology by DrM exhibitsexceptional performance while producing high filtratequality High average flow rates in combination withcyclic operation allows for using smaller filters whichin turn reduces the investment and operating costsdecreases the footprint and reduces the amount ofleachables and extractables

Moreover the CONTIBACreg SU is highly suitable forlarger batch volumes higher cell concentrations andeven continuous production leading the biologicsproduction into a brighter future

References1 Lee B Langer E and Zheng R 2011 Next Generation Single-Use

Bioreactor Technology and the Future of Biomanufacturing ASummary from the Manufacturers and Users Perspective Single-UseTechnology in Biopharmaceutical Manufacture Eibl R Eibl D Wiley-VCH Verlag GmbH Weinheim Germany pp 183-194

2 Moakler B Julkowski K and Dietiker B 2019 October 4 Multi-Cycle Single-Use Filter Optimizes Biopharma Processes InternationalFiltration News Avialble at httpswwwfiltnewscommulti-cycle-single-use-filter-optimizes-biopharma-processes

3 Minow B Egner F and Jonas F et al 2014 High-Cell-DensityClarification By Single-Use Diatomaceous Earth FiltrationBioProcesses International 12(4) pp 36-46

The advantage of using the aforementioned cyclicfiltration technique is that a smaller filter size can beused to perform the same task Unlike conventionalfilters whose capacity is limited by the filter area thecapacity of the CONTIBACreg SU filter is only limitedby the number of cycles or respectively the time theuser has allotted for the filtration A smaller filter alsoleads to a smaller footprint a lower contact area(resulting in less leachables and extractables) as wellas lower investment and operating costs

Case studySuspension growing Chinese Hamster Ovary (CHO)DP-12 cells producing an Immunoglobulin (IgG)-1antibody against Interleukin-8 (clone 1934 ATCCCRL-12445 provided by Prof Dr T Noll BielefeldUniversity Germany) were cultivated in a chemicallydefined medium At the time of the harvest the totaland viable cell densities were 223 and 208 millioncells per ml respectively The solids content was493 gL and the viability was 932 The pH wasreduced from 675 to five prior to the harvest byadding diluted acetic acid and 40 Celpurereg C300filter aid was added per wet cell weight Theexperiments were performed at a pressure of 15 barwith an FDA certified filter media having a nominalpore size of 09 μm

The flow rates obtained over six cycles are shown inFig 2 In each cycle the flow rate started high anddecreased as the cake was growing In conventionalfiltration systems such as depth filters the filtration iscontinued until the flow rates drop very low at whichpoint the filter is replaced On the other hand in theCONTIBACreg SU each filtration cycle is terminatedonce the flow rate drops significantly below the initialflow rate In this case study each cycle wasterminated once the flow rate approached 1000 LMHat which point the filter was back-flushed the filtermedia regenerated and a new cycle was started

After the back-flush the flow rate went back to theinitial level and a high average flow rate of around2000 LMH could be maintained over all six cycles


LIFESCIENCE

Fig 2 Instantaneous and average low rates measured during sixfiltration cycles The flow rate is given as liters per square meter perhour (LMH) and the filtration pressure was 15 bar


globally but some data from the US and EuropeanUnion have given us a rough impression of howsubstantial the socio-economic burden actually isEvery year in the US 99000 patients die based onantibiotic-resistant pathogen-associated hospital-acquired infections (HAIs) In 2006 50000 patientsdied due to two common HAIs (pneumonia andsepsis) and as a result the economic burden wasaround $8b3

Hundreds of thousands of people worldwide(approximately 33000 in the EU) die every year fromthe consequences of infections with resistantbacteria The United Nations warns that deaths willskyrocket if this is not acted on immediatelyAccording to this 10 million people could die from

known that a drop in antibiotic research or even anend would result in them potentially losing the race

One of the reasons contributing to the AMR crisis isthat for almost a decade many big pharmaceuticalcompanies such as Bristol-Myers Squibb andAbbott have withdrawn from any highly expensiveand non-economically reimbursed antibiotic researchand development However this is only one of thecausing factors ndash summarised in Table 1 above arethe different causes of these non-judiciousbehaviours that have led to the global resistome andAMR crisis

The AMR crisis in numbersIt is still a huge challenge to evaluate the exacteconomic impact of resistant bacterial infections


1) Overpopulation enhanced globalmigration and global misuse ofantibiotics by laymen and professionals

2) Excessive use of antibiotics in animals(food pets aquatic)

3) Inadequate hygiene standards inhealth care agriculture food industriesand stock farming etc

4) Senseless cost reduction or ignoringnecessary investigations in health care(eg hospitals)

5) Increased number of class 3 medicaldevices - potential risk of foreignmaterial-associated infections

6) Grossly negligent not to continueresearch and development of new antibiotics

7) Lacking knowledge about AMRmechanisms particularly in context ofFBR-associated colonization biofilmformation and infection

8) Missing or delayed translation andimplementation of alternativecomplementary drug-free antimicrobial strategies

The causes of the fast increasing global resistome and the resulting AMR crisis

AMR Antimicrobial crisis particularly antibiotic crisisFBR Foreign body reaction












+49 234 32 21819







































+49 921 556701














































































6(265) (2014) 265sr6







Res 176(2) (2012) 490-502










+1 412 624-5308






Neurol 51(1) (1999) 99-104



19(3) (2010) 467-76






12(10) (2006) 2949-55






































+41 (0)58 934 55 12




































+44 (0) 1892 613400


























+41 44 921 21 21















LIFESCIENCE













+49 234 32 21819







































+49 921 556701














































































6(265) (2014) 265sr6







Res 176(2) (2012) 490-502










+1 412 624-5308






Neurol 51(1) (1999) 99-104



19(3) (2010) 467-76






12(10) (2006) 2949-55






































+41 (0)58 934 55 12




































+44 (0) 1892 613400


























+41 44 921 21 21















LIFESCIENCE

















+49 921 556701














































































6(265) (2014) 265sr6







Res 176(2) (2012) 490-502










+1 412 624-5308






Neurol 51(1) (1999) 99-104



19(3) (2010) 467-76






12(10) (2006) 2949-55






































+41 (0)58 934 55 12




































+44 (0) 1892 613400


























+41 44 921 21 21















LIFESCIENCE































































6(265) (2014) 265sr6







Res 176(2) (2012) 490-502










+1 412 624-5308






Neurol 51(1) (1999) 99-104



19(3) (2010) 467-76






12(10) (2006) 2949-55






































+41 (0)58 934 55 12




































+44 (0) 1892 613400


























+41 44 921 21 21















LIFESCIENCE





+1 412 624-5308






Neurol 51(1) (1999) 99-104



19(3) (2010) 467-76






12(10) (2006) 2949-55






































+41 (0)58 934 55 12




































+44 (0) 1892 613400


























+41 44 921 21 21















LIFESCIENCE























+41 (0)58 934 55 12




































+44 (0) 1892 613400


























+41 44 921 21 21















LIFESCIENCE




















+44 (0) 1892 613400


























+41 44 921 21 21















LIFESCIENCE


















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LIFESCIENCE



BIOMATERIALS & BIOCERAMICS |PROFILE · 2020. 6. 23. · All of these implants are made of...

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Transcript of BIOMATERIALS & BIOCERAMICS |PROFILE · 2020. 6. 23. · All of these implants are made of...