ASTM F2900-2011 Standard Guide for Characterization of Hydrogels used in Regenerative Medicine《再生医学中使用的水凝胶表征的标准指南》.pdf

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1、Designation: F2900 11Standard Guide forCharacterization of Hydrogels used in RegenerativeMedicine1This standard is issued under the fixed designation F2900; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revision, the year of last revision.

2、 A number in parentheses indicates the year of last reapproval. Asuperscript epsilon () indicates an editorial change since the last revision or reapproval.1. Scope1.1 Hydrogels are water-swollen polymeric networks thatretain water within the spaces between the macromolecules;and maintain the struct

3、ural integrity of a solid due to thepresence of cross-links (1-3).2They are mainly used inregenerative medicine as matrix substitutes, delivery vehiclesfor drugs and/or biologics, and environments for cell culture. Inthese applications, hydrogel efficacy may depend on the abilityto: support the perm

4、eation of dissolved gases, nutrients andbioactive materials; sustain cell growth and migration; de-grade; release drugs and/or biologics at an appropriate rate; andmaintain their shape.1.2 Hydrogels used in regenerative medicine can be com-posed of naturally derived polymers (for example, alginate,c

5、hitosan, collagen (4, 5), synthetically derived polymers (forexample, polyethylene glycol (PEG), polyvinyl alcohol (PVA)(4, 5) or a combination of both (for example, PVA withchitosan or gelatin (6). In clinical use, they can be injected orimplanted into the body with or without the addition of drugs

6、and/or biologics (7).1.3 This guide provides an overview of test methods suit-able for characterizing hydrogels used in regenerative medi-cine. Specifically, this guide describes methods to assesshydrogel biological properties, kinetics of formation, degrada-tion and agent release, physical and chem

7、ical stability andmass transport capabilities are discussed.1.4 The test methods described use hydrated samples withone exception: determining the water content of hydrogelsrequires samples to be dried. It is generally recommended thathydrogels that have been dried for this purpose are notrehydrated

8、 for further testing. This recommendation is due tothe high probability that, for most hydrogel systems, thedrying-rehydration process can be detrimental with possiblealterations in structure.1.5 This guide does not consider evaluation of the micro-structure of hydrogels (for example, matrix morphol

9、ogy, mac-romolecule network structure and chain conformation).1.6 The values stated in SI units are to be regarded asstandard. No other units of measurement are included in thisstandard.1.7 This standard does not purport to address all of thesafety concerns, if any, associated with its use. It is th

10、eresponsibility of the user of this standard to establish appro-priate safety and health practices and determine the applica-bility of regulatory limitations prior to use.2. Referenced Documents2.1 ASTM Standards:3D4516 Practice for Standardizing Reverse Osmosis Perfor-mance DataF748 Practice for Se

11、lecting Generic Biological Test Meth-ods for Materials and DevicesF895 Test Method for Agar Diffusion Cell Culture Screen-ing for CytotoxicityF2027 Guide for Characterization and Testing of Raw orStarting Biomaterials for Tissue-Engineered Medical Prod-uctsF2064 Guide for Characterization and Testin

12、g of Alginatesas Starting Materials Intended for Use in Biomedical andTissue-Engineered Medical Products ApplicationF2103 Guide for Characterization and Testing of ChitosanSalts as Starting Materials Intended for Use in Biomedicaland Tissue-Engineered Medical Product ApplicationsF2150 Guide for Char

13、acterization and Testing of Biomate-rial Scaffolds Used in Tissue-Engineered Medical ProductsF2214 Test Method for In Situ Determination of NetworkParameters of Crosslinked Ultra High Molecular WeightPolyethylene (UHMWPE)F2315 Guide for Immobilization or Encapsulation of LivingCells or Tissue in Alg

14、inate Gels1This guide is under the jurisdiction of ASTM Committee F04 on Medical andSurgical Materials and Devices and is the direct responsibility of SubcommitteeF04.42 on Biomaterials and Biomolecules for TEMPs.Current edition approved March 15, 2011. Published March 2011. DOI:10.1520/F290011.2The

15、 boldface numbers in parentheses refer to a list of references at the end ofthis standard.3For referenced ASTM standards, visit the ASTM website, www.astm.org, orcontact ASTM Customer Service at serviceastm.org. For Annual Book of ASTMStandards volume information, refer to the standards Document Sum

16、mary page onthe ASTM website.1Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.F2347 Guide for Characterization and Testing of Hyaluro-nan as Starting Materials Intended for Use in Biomedicaland Tissue Engineered Medical Product Applic

17、ationsF2383 Guide for Assessment of Adventitious Agents inTissue Engineered Medical Products (TEMPs)F2450 Guide for Assessing Microstructure of PolymericScaffolds for Use in Tissue-Engineered Medical ProductsF2739 Guide for Quantitating Cell Viability Within Bioma-terial Scaffolds2.2 ISO Standards:4

18、ISO 10993 Biological Evaluation of Medical DevicesISO 22442 Medical Devices Utilizing Animal Tissues andTheir Derivatives2.3 ANSI/AAMI Standards:4STBK91 SterilizationPart 1: Sterilization in Health CareFacilitiesSTBK92 SterilizationPart 2: Sterilization EquipmentSTBK93 SterilizationPart 3: Industria

19、l Process ControlST72 Bacterial EndotoxinTest Methodologies, RoutineMonitoring and Alternatives to Batch Testing2.4 Federal Regulations:521 CFR 210 Current Good Manufacturing Practice inManufacturing, Processing, Packaging or Holdings ofDrugs, General21 CFR 221 Current Good Manufacturing Practice fo

20、rFinished Pharmaceuticals21 CFR 610 General Biological Products Standards21 CFR 820 Quality System Regulation3. Terminology3.1 Definitions:3.1.1 adventitious agents, nunintentionally introducedmicrobiological or other infectious contaminant. In the produc-tion of tissue engineered medical products (

21、TEMPs), theseagents may be unintentionally introduced during the manufac-turing process or into the final product or both.3.1.2 biocompatibility, nthe ability of a foreign materialto fulfill its intended function with an appropriate host organ-ism response.3.1.3 conductivity, nproperty of a substanc

22、es (in thiscase, water and dissolved ions) ability to transmit electricity.3.1.3.1 DiscussionConductivity is the inverse of resistiv-ity.3.1.3.2 DiscussionConductivity is measured by a conduc-tivity meter.3.1.3.3 DiscussionThe units of conductivity are Siemensper metre (Sm-1).3.1.4 hydrogel, na thre

23、e-dimensional network of polymerchains that retains water within the spaces between themacromolecules.3.1.5 loss (viscous) modulus, nquantitative measure ofenergy dissipation, defined as the ratio of stress 90 out ofphase with oscillating strains to the magnitude of strain.3.1.6 mechanical propertie

24、s, nthose properties of a mate-rial that are associated with elastic and inelastic reaction whenforces are applied and released. These properties are oftendescribed in terms of constitutive relationship betweenstresses, strains, and strain rates.3.1.7 permittivity, complex, na material property dedu

25、cedfrom the ratio of the admittance, Yp, of a given electrodeconfiguration separated by that material, to the admittance ofthe identical electrode configuration separated by a vacuum orair for most practical purposes, Yv.3.1.8 regenerative medicine, na branch of medical sci-ence that applies the pri

26、nciples of regenerative biology torestore or recreate the structure and function of human cells,tissues, and organs that do not regenerate adequately.3.1.9 relaxation modulus, nthe modulus of a materialdetermined using a strain-controlled (relaxation) experiment attemperature T and time t, which may

27、 also be expressed usingreduced time as E(Tref,j).3.1.10 storage (elastic) modulus, nquantitative measureof elastic properties defined as the ratio of the stress, in-phasewith strain, to the magnitude of the strain.3.1.11 tan delta, nratio of the viscous (loss) modulus tothe elastic (storage) modulu

28、s in a sinusoidal deformation;mathematically, the tangent of the loss angle, d.3.1.12 tomography, nany radiologic technique that pro-vides an image of a selected plane in an object to the relativeexclusion of structures that lie outside the plane of interest.4. Significance and Use4.1 This guide des

29、cribes methods for determining the keyattributes of hydrogels used in regenerative medicine (that is,their biological properties, kinetics of formation, degradationand agent release, physical and chemical stability and masstransport capabilities). See Table 1.5. Key Factors for Hydrogel Characteriza

30、tion5.1 In regenerative medicine, hydrogels can be used withthe addition of drugs or biologics, or both (for example, as drugdelivery devices or for cell encapsulation (4) or without (forexample, as tissue scaffolds or barriers (4). Although charac-terization of hydrogels requires consideration of t

31、he individualcomposition and application the hydrogel will be used for,there are common generic requirements that can be sum-marised as follows:They need to be biocompatible (8).Their mechanical properties should enable them to be compatiblewith their intended clinical use.They should be capable of

32、swelling and potentially degrading at arate that meets the needs of the intended clinical use (9, 10).They should be sufficiently permeable to promote and maintain cellviability, nutrient and waste product transport, or release therapeuticagents, or combination thereof.Hydrogels, when combined with

33、drugs or biologics, including anyseeded or encapsulated cells, should not negatively alter the func-tional characteristics of the biologic or the drug through physical orbiological interactions arising from the presence of hydrogels.Ease of handling and delivery must also be considered sinceit is of

34、 importance for clinical use (4).4Available from American National Standards Institute (ANSI), 25 W. 43rd St.,4th Floor, New York, NY 10036, http:/www.ansi.org.5Available from U.S. Government Printing Office Superintendent of Documents,732 N. Capitol St., NW, Mail Stop: SDE, Washington, DC 20401, ht

35、tp:/www.access.gpo.gov.F2900 112Variability in the composition of the starting polymer mate-rial used in hydrogels impacts the hydrogel final properties. Itis therefore necessary to characterize the starting material,particularly for polymers derived from natural sources due tothe inherent variabili

36、ty of their composition. Guidance oncharacterization of starting biomaterials for TEMPs can befound in Guides F2027, F2064, F2103, and F2347. Further,when hydrogels used in regenerative medicine are preparedunder broad manufacturing conditions, the effect of variableco-agent concentrations and the e

37、ffect of variable manufactur-ing conditions (for example, pH, temperature, ionic strength)on the final hydrogel properties should be considered andmeasured as appropriate.5.2 The degree of hydrogel crosslinking is an importantparameter affecting hydrogel physical properties and perfor-mance. Correla

38、tion between the stoichiometric and effectivedegree of crosslinking in the final hydrogel is a direct indica-tion of the extent of reaction. In some cases determination ofcrosslinking is not trivial and it is therefore recommended thatan estimation of percent post-gelation extractables should beperf

39、ormed. This will serve as a direct indicator for thecrosslinking efficiency and will provide information on poten-tially harmful leachables.5.3 Sterilization processes can affect the properties of thehydrogel or any active or inactive added components, or both(for example, drug, excipient, and so fo

40、rth), all of which needto be taken into account when considering characterizationdata. In order to appropriately assess hydrogel characterizationdata, it is recommended that a sterilization summary is pro-vided along with the sample. Further guidance on sterilizationstrategies can be found in Guide

41、F2150, STBK91, STBK92,and STBK93. It is noted, however, that a particular steriliza-tion method may not be applicable to a certain type ofhydrogel. In this case, provision of non-sterile hydrogels in amedium that contains antimicrobial agents or producing hy-drogels under aseptic conditions may need

42、 to be consideredwith additional controls such as bioburden reduction andsterility testing.5.4 It may be possible to assess the hydrogel response to invivo conditions through the use of suitable ex vivo models.Factors that such models should take into consideration in-clude: tissue-specific mechanic

43、al loading; tissue-specific meta-bolic activity; tissue-specific pH; relevant chemistry to thesite/condition of implantation; temperature; oxygen content;and tissue-specific cell types present. For example, the testingof ionically crosslinked hydrogels which are susceptible to ionexchange during imp

44、lantation (for example, Ca2+crosslinkedalginates) should be done in media resembling the physiologi-cal environment at least in terms of electrolytic content andosmolarity and the relevant chemistry such as divalent cationdelivery. For temperature-sensitive hydrogels, the hydrogelgelling temperature

45、 is key to assess in vivo performance, andtests should be carried out at 37C. For gels implanted ininterstitial fluid, fat tissues, and so forth, in addition tomaintaining a physiologically relevant electrolytic balance,testing may need to be done in serum, or at least in the presenceof proteins and

46、 lipids, and so forth.5.5 Consideration should be given to hydrogel stabilityduring storage and transportation. It may be necessary tomaintain hydrogels in a controlled environment with factorssuch as temperature and pH regulated.5.6 To adequately assess the suitability of a candidatehydrogel for us

47、e in regenerative medicine it is necessary toconsider the key factors identified in Table 1. Each factor canbe assessed through measurement of different hydrogel prop-erties that will be discussed below. In all cases measuredquantities should be reported in the relevant SI units.6. Biological Proper

48、ties6.1 BiocompatibilityThe biocompatibility of the hydrogelproduct shall be established. Currently there are no standardsthat describe protocols specifically for hydrogels; however,guidance on test methods can be found in Practice F748 or inISO 10993.6.2 Adventitious AgentsHydrogels containing poly

49、mersderived from natural sources and those that contain biologicsneed to be assessed for safety associated with adventitiousagents and their by-products. Guidelines for microbiologicaltesting of aerobic and anaerobic bacteria, fungi, mycoplasma,endotoxins and viruses are given in 21 CFR 610. Test methodsfor determining the presence of bacterial endotoxins are alsogiven in ST72. The ISO 22442 series is also useful as itprovides guidance on risk management related to hazards suchas contamination by bacteria and viruses as well as materialsresponsibl