Injectable, Biodegradable Hydrogels for Tissue Engineering Applications

Hydrogels have many different applications in the field of regenerative medicine. Biodegradable, injectable hydrogels could be utilized as delivery systems, cell carriers, and scaffolds for tissue engineering. Injectable hydrogels are an appealing scaffold because they are structurally similar to the extracellular matrix of many tissues, can often be processed under relatively mild conditions, and may be delivered in a minimally invasive manner. This review will discuss recent advances in the field of injectable hydrogels, including both synthetic and native polymeric materials, which can be potentially used in cartilage and soft tissue engineering applications.

[1]  L. Peer.  THE NEGLECTED FREE FAT GRAFT , 1956, Plastic and reconstructive surgery.

[2]  R. Timpl,et al.  Immunochemistry of collagens and procollagens. , 1976, International review of connective tissue research.

[3]  I. Yannas,et al.  Design of an artificial skin. I. Basic design principles. , 1980, Journal of biomedical materials research.

[4]  S. Kumar,et al.  Hyaluronan and angiogenesis. , 1989, Ciba Foundation symposium.

[5]  G. Skjåk-Bræk,et al.  Inhomogeneous polysaccharide ionic gels , 1989 .

[6]  B. Toole.  Hyaluronan and its binding proteins, the hyaladherins. , 1990, Current opinion in cell biology.

[7]  K. Goa,et al.  Hyaluronic acid. A review of its pharmacology and use as a surgical aid in ophthalmology, and its therapeutic potential in joint disease and wound healing. , 1994, Drugs.

[8]  M. Laus,et al.  Evaluation of poly(vinyl alcohol) hydrogels as a component of hybrid artificial tissues , 1995 .

[9]  Charles A. Vacanti,et al.  Injectable cartilage. Discussion , 1995 .

[10]  L G Cima,et al.  Injectable Cartilage , 1995, Plastic and reconstructive surgery.

[11]  Yoshimitsu Kuroyanagi,et al.  Design of artificial skin , 1996 .

[12]  J. Vacanti,et al.  De Novo Cartilage Generation Using Calcium Alginate‐Chondrocyte Constructs , 1996, Plastic and reconstructive surgery.

[13]  E. Turley,et al.  HA receptors: Regulators of signalling to the cytoskeleton , 1996, Journal of cellular biochemistry.

[14]  W. Hayes,et al.  Characterization of partially saturated poly(propylene fumarate) for orthopaedic application. , 1997, Journal of biomaterials science. Polymer edition.

[15]  J. Fraser,et al.  Hyaluronan: its nature, distribution, functions and turnover , 1997, Journal of internal medicine.

[16]  H. Sung,et al.  Feasibility study of a natural crosslinking reagent for biological tissue fixation. , 1998, Journal of biomedical materials research.

[17]  C. Helmick,et al.  Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. , 1998, Arthritis and rheumatism.

[18]  M. Radice,et al.  Semisynthetic resorbable materials from hyaluronan esterification. , 1998, Biomaterials.

[19]  A. Mikos,et al.  In vivo degradation of a poly(propylene fumarate)/beta-tricalcium phosphate injectable composite scaffold. , 1998, Journal of biomedical materials research.

[20]  R. Verbeeck,et al.  Synthesis and thermal properties of poly(ethylene glycol)-poly(?-caprolactone) copolymers , 1998 .

[21]  Andrew A. Pitsillides,et al.  An Essential Role for the Interaction Between Hyaluronan and Hyaluronan Binding Proteins During Joint Development , 1998, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[22]  Kevin E. Healy,et al.  Synthesis and characterization of injectable poly(N-isopropylacrylamide)-based hydrogels that support tissue formation in vitro , 1999 .

[23]  D J Mooney,et al.  Alginate hydrogels as synthetic extracellular matrix materials. , 1999, Biomaterials.

[24]  T. Cruz,et al.  Receptor for hyaluronan-mediated motility (RHAMM), a hyaladherin that regulates cell responses to growth factors. , 1999, Biochemical Society transactions.

[25]  Linshu Liu,et al.  An osteoconductive collagen/hyaluronate matrix for bone regeneration. , 1999, Biomaterials.

[26]  M. Spector,et al.  Meniscus cells seeded in type I and type II collagen-GAG matrices in vitro. , 1999, Biomaterials.

[27]  H. Sung,et al.  In vitro evaluation of the genotoxicity of a naturally occurring crosslinking agent (genipin) for biologic tissue fixation. , 2000, Journal of biomedical materials research.

[28]  C. Cooper,et al.  Risk factors for the incidence and progression of radiographic knee osteoarthritis. , 2000, Arthritis and rheumatism.

[29]  A. Mikos,et al.  Injectable biodegradable materials for orthopedic tissue engineering. , 2000, Biomaterials.

[30]  J. Leroux,et al.  Novel injectable neutral solutions of chitosan form biodegradable gels in situ. , 2000, Biomaterials.

[31]  S. Shenaq,et al.  Increased Free Fat‐Graft Survival with the Long‐Term, Local Delivery of Insulin, InsulinLike Growth Factor‐I, and Basic Fibroblast Growth Factor by PLGA/PEG Microspheres , 2000, Plastic and reconstructive surgery.

[32]  J. Elisseeff,et al.  Photoencapsulation of chondrocytes in poly(ethylene oxide)-based semi-interpenetrating networks. , 2000, Journal of biomedical materials research.

[33]  A. Mikos,et al.  Injectable biodegradable polymer composites based on poly(propylene fumarate) crosslinked with poly(ethylene glycol)-dimethacrylate. , 2000, Biomaterials.

[34]  A. Mikos,et al.  Marrow stromal osteoblast function on a poly(propylene fumarate)/beta-tricalcium phosphate biodegradable orthopaedic composite. , 2000, Biomaterials.

[35]  Y. Bae,et al.  In situ gelation of PEG-PLGA-PEG triblock copolymer aqueous solutions and degradation thereof. , 2000, Journal of biomedical materials research.

[36]  P. Ma,et al.  Ionically crosslinked alginate hydrogels as scaffolds for tissue engineering: part 1. Structure, gelation rate and mechanical properties. , 2001, Biomaterials.

[37]  Dong Wang,et al.  Rheological characterisation of thermogelling chitosan/glycerol-phosphate solutions , 2001 .

[38]  Antonios G. Mikos,et al.  Synthesis and Characterization of Oligo(poly(ethylene glycol) fumarate) Macromer , 2001 .

[39]  Y. Nakayama,et al.  Thermoresponsive artificial extracellular matrix for tissue engineering: hyaluronic acid bioconjugated with poly(N-isopropylacrylamide) grafts. , 2001, Biomacromolecules.

[40]  Yugyung Lee,et al.  Biomedical applications of collagen. , 2001, International journal of pharmaceutics.

[41]  Eben Alsberg,et al.  Degradation of Partially Oxidized Alginate and Its Potential Application for Tissue Engineering , 2001, Biotechnology progress.

[42]  O. Damour,et al.  Influence of the degree of acetylation on some biological properties of chitosan films. , 2001, Biomaterials.

[43]  J O Hollinger,et al.  Controlled Release from Coated Polymer Microparticles Embedded in Tissue-engineered Scaffolds , 2001, Journal of drug targeting.

[44]  J. Chen,et al.  A preliminary in vitro study on the fabrication and tissue engineering applications of a novel chitosan bilayer material as a scaffold of human neofetal dermal fibroblasts. , 2001, Biomaterials.

[45]  K. Anseth,et al.  Attachment of fibronectin to poly(vinyl alcohol) hydrogels promotes NIH3T3 cell adhesion, proliferation, and migration. , 2001, Journal of biomedical materials research.

[46]  H. Sung,et al.  In vitro evaluation of a chitosan membrane cross-linked with genipin , 2001, Journal of biomaterials science. Polymer edition.

[47]  D. Mooney,et al.  Hydrogels for tissue engineering. , 2001, Chemical Reviews.

[48]  Yu-Ling Cheng,et al.  In-Situ Thermoreversible Gelation of Block and Star Copolymers of Poly(ethylene glycol) and Poly(N-isopropylacrylamide) of Varying Architectures , 2001 .

[49]  J. Hubbell,et al.  Systematic modulation of Michael-type reactivity of thiols through the use of charged amino acids. , 2001, Bioconjugate chemistry.

[50]  Seon Jeong Kim,et al.  Rapid temperature/pH response of porous alginate-g-poly(N-isopropylacrylamide) hydrogels , 2002 .

[51]  A. Fokin,et al.  Poland's syndrome revisited. , 2002, The Annals of thoracic surgery.

[52]  H. Sung,et al.  In vivo evaluation of cellular and acellular bovine pericardia fixed with a naturally occurring crosslinking agent (genipin). , 2002, Biomaterials.

[53]  J. Hubbell,et al.  Materials for Cell Encapsulation via a New Tandem Approach Combining Reverse Thermal Gelation and Covalent Crosslinking. , 2002 .

[54]  Stephanie J Bryant,et al.  In situ forming degradable networks and their application in tissue engineering and drug delivery. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[55]  Mitsuo Umezu,et al.  Fabrication of Pulsatile Cardiac Tissue Grafts Using a Novel 3-Dimensional Cell Sheet Manipulation Technique and Temperature-Responsive Cell Culture Surfaces , 2002, Circulation research.

[56]  Liqun Wang,et al.  Synthesis and characterization of temperature responsive graft copolymers of dextran with poly(N-isopropylacrylamide) , 2002 .

[57]  P. Pudney,et al.  Mechanism and kinetics of the crosslinking reaction between biopolymers containing primary amine groups and genipin , 2003 .

[58]  Jeffrey A Hubbell,et al.  Photopolymerized hyaluronic acid-based hydrogels and interpenetrating networks. , 2003, Biomaterials.

[59]  Antonios G Mikos,et al.  In vivo bone and soft tissue response to injectable, biodegradable oligo(poly(ethylene glycol) fumarate) hydrogels. , 2003, Biomaterials.

[60]  J. Hubbell,et al.  Water-borne, in situ crosslinked biomaterials from phase-segregated precursors. , 2003, Journal of biomedical materials research. Part A.

[61]  V. Sikavitsas,et al.  Quantification of ligand surface concentration of bulk-modified biomimetic hydrogels. , 2003, Biomaterials.

[62]  D. Mooney,et al.  Hydrogel Formation via Cell Crosslinking , 2003 .

[63]  S. Hsu,et al.  In vitro evaluation of degradation and cytotoxicity of a novel composite as a bone substitute. , 2003, Journal of biomedical materials research. Part A.

[64]  J. Mao,et al.  Study of novel chitosan-gelatin artificial skin in vitro. , 2003, Journal of biomedical materials research. Part A.

[65]  J. Hubbell,et al.  Synthesis and physicochemical characterization of end-linked poly(ethylene glycol)-co-peptide hydrogels formed by Michael-type addition. , 2003, Biomacromolecules.

[66]  D. Mooney,et al.  Hydrogels for tissue engineering: scaffold design variables and applications. , 2003, Biomaterials.

[67]  T. Matsuda,et al.  Tissue-engineered cartilage using an injectable and in situ gelable thermoresponsive gelatin: fabrication and in vitro performance. , 2003, Tissue engineering.

[68]  Takashi Inamoto,et al.  Adipose tissue engineering based on human preadipocytes combined with gelatin microspheres containing basic fibroblast growth factor. , 2003, Biomaterials.

[69]  J. A. Hubbell,et al.  Cell‐Responsive Synthetic Hydrogels , 2003 .

[70]  Antonios G Mikos,et al.  Transforming growth factor-beta 1 release from oligo(poly(ethylene glycol) fumarate) hydrogels in conditions that model the cartilage wound healing environment. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[71]  K. Marra,et al.  Biodegradable poly(ethylene glycol) hydrogels crosslinked with genipin for tissue engineering applications. , 2004, Journal of biomedical materials research. Part B, Applied biomaterials.

[72]  Stephanie J Bryant,et al.  Encapsulating chondrocytes in degrading PEG hydrogels with high modulus: Engineering gel structural changes to facilitate cartilaginous tissue production , 2004, Biotechnology and bioengineering.

[73]  G. Ryu,et al.  Synthesis and characterization of thermosensitive chitosan copolymer as a novel biomaterial , 2004, Journal of biomaterials science. Polymer edition.

[74]  N. Peppas,et al.  Structure and Interactions in Covalently and Ionically Crosslinked Chitosan Hydrogels for Biomedical Applications , 2003 .

[75]  K. Shakesheff,et al.  Injectable scaffolds for tissue regeneration , 2004 .

[76]  Christine E Schmidt,et al.  Development of photocrosslinkable hyaluronic acid-polyethylene glycol-peptide composite hydrogels for soft tissue engineering. , 2004, Journal of biomedical materials research. Part A.

[77]  S. Bryant,et al.  Crosslinking density influences the morphology of chondrocytes photoencapsulated in PEG hydrogels during the application of compressive strain , 2004, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[78]  A. Jayakrishnan,et al.  Preparation and in vitro evaluation of primaquine-conjugated gum arabic microspheres. , 2004, Biomacromolecules.

[79]  Kristyn S Masters,et al.  Designing scaffolds for valvular interstitial cells: cell adhesion and function on naturally derived materials. , 2004, Journal of biomedical materials research. Part A.

[80]  Su-Hyang Kim,et al.  Chondrogenic differentiation of human mesenchymal stem cells using a thermosensitive poly(N-isopropylacrylamide) and water-soluble chitosan copolymer. , 2004, Biomaterials.

[81]  Robert Langer,et al.  A rapid-curing alginate gel system: utility in periosteum-derived cartilage tissue engineering. , 2004, Biomaterials.

[82]  Seon Jeong Kim,et al.  Temperature/pH‐sensitive comb‐type graft hydrogels composed of chitosan and poly(N‐isopropylacrylamide) , 2004 .

[83]  Farshid Guilak,et al.  Chondrogenic differentiation of adipose-derived adult stem cells in agarose, alginate, and gelatin scaffolds. , 2004, Biomaterials.

[84]  Eben Alsberg,et al.  Controlling Degradation of Hydrogels via the Size of Crosslinked Junctions , 2004, Advanced materials.

[85]  Kristi S Anseth,et al.  Encapsulating chondrocytes in copolymer gels: bimodal degradation kinetics influence cell phenotype and extracellular matrix development. , 2004, Journal of biomedical materials research. Part A.

[86]  Ralph Müller,et al.  Synthetic extracellular matrices for in situ tissue engineering , 2004, Biotechnology and bioengineering.

[87]  T. Sheffield,et al.  In vitro osteogenic differentiation of marrow stromal cells encapsulated in biodegradable hydrogels. , 2004, Journal of biomedical materials research. Part A.

[88]  D. Seliktar,et al.  Biosynthetic hydrogel scaffolds made from fibrinogen and polyethylene glycol for 3D cell cultures. , 2005, Biomaterials.

[89]  Joao Maia,et al.  Synthesis and characterization of new injectable and degradable dextran-based hydrogels , 2005 .

[90]  Xiaochen Shen,et al.  pH-induced self-assembly and capsules of sodium alginate. , 2005, Biomacromolecules.

[91]  Yan Huang,et al.  In vitro characterization of chitosan-gelatin scaffolds for tissue engineering. , 2005, Biomaterials.

[92]  M. Horne,et al.  Morphology and gelation of thermosensitive chitosan hydrogels. , 2005, Biophysical chemistry.

[93]  A. Jayakrishnan,et al.  Self-cross-linking biopolymers as injectable in situ forming biodegradable scaffolds. , 2005, Biomaterials.

[94]  Kristi L Kiick,et al.  Rheological characterization of polysaccharide-poly(ethylene glycol) star copolymer hydrogels. , 2005, Biomacromolecules.

[95]  Miqin Zhang,et al.  PEG-grafted chitosan as an injectable thermosensitive hydrogel for sustained protein release. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[96]  Jennifer L West,et al.  Covalent immobilization of RGDS on hydrogel surfaces to direct cell alignment and migration. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[97]  Mizuo Maeda,et al.  DNA-responsive hydrogels that can shrink or swell. , 2005, Biomacromolecules.

[98]  A. Hoffman,et al.  Semi-interpenetrating network of poly(ethylene glycol) and poly(D, L-lactide) for the controlled delivery of protein drugs , 2005, Journal of biomaterials science. Polymer edition.

[99]  M D McKee,et al.  Tissue engineering of cartilage using an injectable and adhesive chitosan-based cell-delivery vehicle. , 2005, Osteoarthritis and cartilage.

[100]  J. Hartgerink,et al.  Modulation of peptide-amphiphile nanofibers via phospholipid inclusions. , 2006, Biomacromolecules.

[101]  J. Kobler,et al.  Hyaluronic acid-based microgels and microgel networks for vocal fold regeneration. , 2006, Biomacromolecules.

[102]  Ick Chan Kwon,et al.  Biodegradability and biocompatibility of a pH- and thermo-sensitive hydrogel formed from a sulfonamide-modified poly(epsilon-caprolactone-co-lactide)-poly(ethylene glycol)-poly(epsilon-caprolactone-co-lactide) block copolymer. , 2006, Biomaterials.

[103]  K. Marra,et al.  Controlled in vivo degradation of genipin crosslinked polyethylene glycol hydrogels within osteochondral defects. , 2006, Tissue engineering.

[104]  Zhiyuan Zhong,et al.  In-situ formation of biodegradable hydrogels by stereocomplexation of PEG-(PLLA)8 and PEG-(PDLA)8 star block copolymers. , 2006, Biomacromolecules.

[105]  Jia-cong Shen,et al.  Covalently crosslinked chitosan hydrogel formed at neutral pH and body temperature. , 2006, Journal of biomedical materials research. Part A.

[106]  K. Marra,et al.  Controlled release of bioactive TGF-beta 1 from microspheres embedded within biodegradable hydrogels. , 2006, Biomaterials.

[107]  F. Szoka,et al.  Efficient synthesis of an aldehyde functionalized hyaluronic acid and its application in the preparation of hyaluronan-lipid conjugates. , 2006, Bioconjugate chemistry.

[108]  Jyh-Ping Chen,et al.  Thermo-responsive chitosan-graft-poly(N-isopropylacrylamide) injectable hydrogel for cultivation of chondrocytes and meniscus cells. , 2006, Macromolecular bioscience.

[109]  Sang Bong Lee,et al.  Preparation of thermo-responsive and injectable hydrogels based on hyaluronic acid and poly(N-isopropylacrylamide) and their drug release behaviors , 2006 .

[110]  Lonnie D Shea,et al.  Non-viral vector delivery from PEG-hyaluronic acid hydrogels. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[111]  Changyou Gao,et al.  Gelatin/chitosan/hyaluronan ternary complex scaffold containing basic fibroblast growth factor for cartilage tissue engineering , 2007, Journal of materials science. Materials in medicine.

[112]  K. Anseth,et al.  Multifunctional Pancreatic Islet Encapsulation Barriers Achieved via Multilayer PEG Hydrogels , 2007, Cell transplantation.

[113]  E. Chaikof,et al.  Bouquet-type dendrimerlike poly(ethylene oxide)s with a focal aldehyde and peripheral hydroxyls. , 2007, Biomacromolecules.

[114]  D. Discher,et al.  Cell responses to the mechanochemical microenvironment--implications for regenerative medicine and drug delivery. , 2007, Advanced drug delivery reviews.

[115]  Stephanie J Bryant,et al.  Mechanical stimulation of TMJ condylar chondrocytes encapsulated in PEG hydrogels. , 2007, Journal of biomedical materials research. Part A.

[116]  Achim Goepferich,et al.  Rational design of hydrogels for tissue engineering: impact of physical factors on cell behavior. , 2007, Biomaterials.

[117]  C. Highley,et al.  The prevention of peritoneal adhesions by in situ cross-linking hydrogels of hyaluronic acid and cellulose derivatives. , 2007, Biomaterials.

[118]  J. Feijen,et al.  In vitro and in vivo protein delivery from in situ forming poly(ethylene glycol)-poly(lactide) hydrogels. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[119]  Shyni Varghese,et al.  Multifunctional chondroitin sulphate for cartilage tissue-biomaterial integration. , 2007, Nature materials.

[120]  J. Rubin,et al.  Collagenous Microbeads as a Scaffold for Tissue Engineering with Adipose-Derived Stem Cells , 2007, Plastic and reconstructive surgery.

[121]  Shang-Ming Lin,et al.  Morphology and characterization of 3D micro-porous structured chitosan scaffolds for tissue engineering. , 2007, Colloids and surfaces. B, Biointerfaces.

[122]  J. Ong,et al.  The effect of cross-linking of chitosan microspheres with genipin on protein release , 2007 .

[123]  R. Kamm,et al.  Primary sequence of ionic self-assembling peptide gels affects endothelial cell adhesion and capillary morphogenesis. , 2008, Journal of biomedical materials research. Part A.

[124]  Shyni Varghese,et al.  Chondroitin sulfate based niches for chondrogenic differentiation of mesenchymal stem cells. , 2008, Matrix biology : journal of the International Society for Matrix Biology.

[125]  Changyou Gao,et al.  Photoinitiating Polymerization to Prepare Biocompatible Chitosan Hydrogels , 2008 .

[126]  S. Bryant,et al.  Cell encapsulation in biodegradable hydrogels for tissue engineering applications. , 2008, Tissue engineering. Part B, Reviews.

[127]  Gregory A Hudalla,et al.  An approach to modulate degradation and mesenchymal stem cell behavior in poly(ethylene glycol) networks. , 2008, Biomacromolecules.

[128]  F. Szoka,et al.  PEGylated dendrimers with core functionality for biological applications. , 2008, Bioconjugate chemistry.

[129]  Changyou Gao,et al.  Microscale control over collagen gradient on poly(L-lactide) membrane surface for manipulating chondrocyte distribution. , 2008, Colloids and surfaces. B, Biointerfaces.

[130]  P. Blondeel,et al.  Autologous in vivo adipose tissue engineering in hyaluronan-based gels--a pilot study. , 2008, The Journal of surgical research.

[131]  Kristi S Anseth,et al.  Macromolecular Monomers for the Synthesis of Hydrogel Niches and Their Application in Cell Encapsulation and Tissue Engineering. , 2008, Progress in polymer science.

[132]  Lin Yu,et al.  Injectable hydrogels as unique biomedical materials. , 2008, Chemical Society reviews.

[133]  Changyou Gao,et al.  Biomimetic modification of chitosan with covalently grafted lactose and blended heparin for improvement of in vitro cellular interaction , 2008 .

[134]  Stephen F Badylak,et al.  FGF-2 Enhances Vascularization for Adipose Tissue Engineering , 2008, Plastic and reconstructive surgery.

[135]  J. Elisseeff,et al.  Keratocyte behavior in three-dimensional photopolymerizable poly(ethylene glycol) hydrogels. , 2008, Acta biomaterialia.

[136]  Zu-wei Ma,et al.  Protein-reactive, thermoresponsive copolymers with high flexibility and biodegradability. , 2008, Biomacromolecules.

[137]  David J Beebe,et al.  An adaptable hydrogel array format for 3-dimensional cell culture and analysis. , 2008, Biomaterials.

[138]  Changyou Gao,et al.  RGD modified PLGA/gelatin microspheres as microcarriers for chondrocyte delivery. , 2009, Journal of biomedical materials research. Part B, Applied biomaterials.

[139]  G. Guo,et al.  Cell adhesion and accelerated detachment on the surface of temperature-sensitive chitosan and poly(N-isopropylacrylamide) hydrogels , 2009, Journal of materials science. Materials in medicine.

[140]  K. Marra,et al.  Injectable in situ forming biodegradable chitosan-hyaluronic acid based hydrogels for cartilage tissue engineering. , 2009, Biomaterials.

[141]  Changyou Gao,et al.  Gelatin/chitosan/hyaluronan scaffold integrated with PLGA microspheres for cartilage tissue engineering. , 2009, Acta biomaterialia.

[142]  Yongjun Zhang,et al.  In situ gelation of P(NIPAM-HEMA) microgel dispersion and its applications as injectable 3D cell scaffold. , 2009, Biomacromolecules.

[143]  J. Rubin,et al.  Thermosensitive injectable hyaluronic acid hydrogel for adipose tissue engineering. , 2009, Biomaterials.

[144]  J. Rubin,et al.  Novel multiarm PEG-based hydrogels for tissue engineering. , 2009, Journal of biomedical materials research. Part A.