engineering of materials for biomedical applications

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Engineering of Materials for Biomedical Applications Kay C Dee, Department of Biomedical Engineering, Tulane University, New Orleans, LA 70118, USA, David Puleo, Center For Biomedical Engineering, University of Kentucky, Lexington, KY, USA and Rena Bizios, Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA Introduction According to the National Center for Health Statistics, an estimated 11 mil- lion Americans had at least one med- ical device implant in 19881 . This number has undoubtedly increased since 1988, and will probably contin- ue to do so, due to increased longevi- ty and advances in implant technolo- gy. In many medical applications, an ideal implant would quickly inte- grate with a patient's tissue and maintain close proximity to the tis- sue over time, thereby avoiding clini- cal problems such as loosening of the implant, pain, destruction of tis- sue near the implant site, and subse- quent (painful and costly) revision surgery. Many scientists and engi- neers are currently working to devel- op such an ideal implant; such endeavors are motivated by the underlying thesis that quick healing and maintenance of tissue could be achieved by "engineering" an implant biomaterial to control select cell functions (such as adhesion, prolifer- ation, differentiation, and deposition of matrix) at the tissue-biomaterial interface. Restating this fundamental thesis in general terms yields the fol- lowing idea: macroscopic, tissue- level events are ultimately derived from, and thus could be controlled by, cellular- and molecular-level events at the tissue-implant inter- face. Therefore, a thorough under- standing of how cells interact with materials is a necessary and cru- cial prerequisite.for the development of novel methods to control cell-biomaterial, and eventually tis- sue-biomaterial, interactions. As an example, consider the implanta- tion of a dental or orthopedic implant. While the interface between bone cells and a (usually metallic) orthopedic/dental biomaterial may initially seem to be a simple meeting of cell membrane and metal, the actu- al cell-material interface is dynamic and complex (Figure 1A). Due to machining, cleaning, and sterilizing processes, as well as exposure to air and to the biological milieu, the sur- face of a metallic implant is an oxide layer; in other words, the composition of the biomaterial surface is different than that of the bulk material. In the physiological environment, serum proteins will quickly adsorb to the surface oxide, creating a protein layer which can vary widely in composi- tion over time. If the correct ligands are present as domains of the G ® Please address correspondence to: Kay C Dee, Phone: 504-865-5893, Fax: 504-862-8779, Email: [email protected] Materials Today 7

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Engineering of Materials for Biomedical Applications Kay C Dee, Department of Biomedical Engineering, Tulane University, New Orleans, LA 70118, USA, David Puleo, Center For Biomedical Engineering, University of Kentucky, Lexington, KY, USA and Rena Bizios, Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA

Introduction According to the National Center for Health Statistics, an estimated 11 mil- lion Americans had at least one med- ical device implant in 19881 . This

n u m b e r has undoubted ly increased since 1988, and will probably contin- ue to do so, due to increased longevi- ty and advances in implant technolo- gy. In many medical applications, an ideal implant would quickly inte- grate wi th a pa t ien t ' s t issue and maintain close proximity to the tis- sue over time, thereby avoiding clini- cal problems such as loosening of the implant, pain, des t ruct ion of tis- sue near the implant site, and subse- quent (painful and costly) revision surgery. Many scientists and engi- neers are current ly working to devel- op such an ideal implant ; such

endeavors are mot iva ted by the under lying thesis that quick healing and main tenance of tissue could be achieved by "engineering" an implant b iomater ia l to cont ro l select cell funct ions (such as adhesion, prolifer- ation, differentiation, and deposi t ion of matrix) at the tissue-biomaterial interface. Restating this fundamenta l thesis in general terms yields the fol- lowing idea: macroscopic , tissue-

level events are u l t imate ly derived

f rom, an d thus could be controlled by, cellular- a n d molecular- leve l

events at the t issue- implant inter-

face. Therefore, a thorough under- s t and ing of how cells in te rac t with materials is a necessary and cru- cial prerequisite.for the deve lopment of novel me t hods to con t ro l cell-biomaterial, and eventually tis- sue-biomaterial, interactions.

As an example, consider the implanta- t ion of a denta l or o r thoped ic implant. While the interface be tween bone cells and a (usually metallic) o r thoped ic /den ta l b iomater ia l may initially seem to be a simple meet ing of cell membrane and metal, the actu- al cell-material interface is dynamic and complex (Figure 1A). Due to machining, cleaning, and sterilizing processes, as well as exposure to air and to the biological milieu, the sur- face of a metallic implant is an oxide layer; in other words, the composi t ion of the biomaterial surface is different than that of the bulk material. In the physiological e n v i r o n m e n t , se rum proteins will quickly adsorb to the surface oxide, creating a protein layer

which can vary widely in composi- t ion over time. If the correct ligands are p resen t as domains of the

G ®

Please address correspondence to: Kay C Dee, Phone: 504-865-5893, Fax: 504-862-8779, Email: [email protected]

Materials Today 7

adsorbed proteins, and these bioac- tive protein domains are in the cor- rect conformat ions , then cell m e m b r a n e receptors" will in teract selectively with the ligands. If the appropriate types and numbers of receptor- l igand complexes are formed, signals are sent to the cell nucleus via cascades of intracellular chemical reactions, and consequent ly cell functions (such as adhesion, dif- ferent iat ion, depos i t ion of matrix, etc.) are regulated (Figure 1B).

Current Efforts to Control Cell- Biomaterial Interactions Following the rationale that healing and main tenance of healthy tissue around an implant are phenomena derived from cellular- and molecular- level processes (such as cell adhesion, proliferation, and intracellular signal- ing), much cur ren t biological and materials eng inee r ing research is devoted to unders tanding and con- trolling these processes. It is impor- tant to recognize that due to the unique characteristics of the biologi- cal environment , events at the tissue- implant interface can produce effects over a wide range of physical scales - from the systemic (whole organism) to the subcellular (molecular) level.

For example, because of the various mechanisms of exchange be tween

tissues and organs, biomaterial degra- dation byproducts can be spread via the circulation to cause systemic or remote site effects. Depending on the ul t imate b iomedica l appl icat ion, designing materials with enhanced resistance to degradation, or which utilize different degradat ion pathways, could reduce these large- scale, systemic problems.

At the level of tissues and organs, w o u n d heal ing and in f l ammatory responses determine the fate of an implanted biomaterial. Some investi- gators are using surface chemistry in attempts to unders tand and control the behavior of macrophages (cells which play a key role in the inflam- matory response to biomaterials) .

Macrophage adhes ion and subse- quent fusion to form giant cells, one character is t ic of a "foreign body response" to an implant , can be altered by factors such as the orienta- t ion of pept ides 2 or the length of hydrocarbon chains 3 immobil ized on the surface of biomaterials . By reducing the foreign body response, chronic and adverse w o u n d healing react ions w h i c h compromise the biostability of the implant may be pre- vented. It should be noted that the progress ion of tissue-level, w o u n d healing responses to an implant can be very sensitive to smaller-scale phe- nomena. For example, subtle changes in polymer chemistry (such as varying the structure of an alkyl ester pendan t chain from ethyl to octyl) can

8 Materials Today

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predictably immobilize bioactive mol- ecules on mater ial surfaces. Fundamental studies are required to develop these n e w materials and techniques, in order to obtain the optimal quantit ies and conformations ( therefore, bioact ivi ty) of pep t ides /p ro t e in s immobi l i zed on materials. Micropatterning techniques (Figure 4) can complemen t biomolec- ular modif ica t ion of materials,

because a particular spatial distribu- t ion of biomolecules may be needed to elicit the desired cellular respons- es. By controll ing spatial aspects of surface biochemistry, cell a t tachment and other cellular responses to the mic ropa t t e rned materials can be man ipu la ted 8-11 (Figure 5). While

de te rmin ing the most appropr ia te surface pat terns and chemistries will likely depend on the eventual physio- logical application, further develop- ment of lithographic and microcon- tact pr int ing processes for biomedical uses will cer ta inly e n h a n c e these research efforts.

dramatically change the tissue response to a polymeric material, resulting in the formation of fibrous rather than bone tissue 4 (Figure 2).

With enough fundamental knowledge about tissue-level react ions to implants, novel biomaterials can be designed to achieve specific, desired wound healing responses.

At the cellular level, porous scaffolds

of biodegradable polymers are being deve loped to possess surface chemistr ies and th ree-d imens iona l microarchi tectures which are sup-

portive of cell infiltration and differ- ent iat ion. These scaffold materials can serve as a temporary structure that is infused with living cells, and is eventually replaced with native tis- sue: these are the materials and bio- logical bases for the field of "tissue engineering". Solid, nonporous sub- strates can be microtextured, using techniques adapted from the elec- tronics industry, to direct cell motility or alter cell functions. For example, cells will migrate along appropriate- ly-sized grooves, and bone tissue for- mation can be a funct ion of surface topography 5. These are undoubted ly

research avenues of great promise and potent ia l . However, opt imal microarch i tec tura l pa ramete rs for con t ro l l ing cellular-level events remain currently undefined. It is like- ly that the definit ion of these param- eters will ultimately depend on the eventual, end-point biomedical appli- cations.

At the physical scale of proteins,

porous matrices and solid substrates are being modified to present chemi- cal "cues" - usually bioactive mole- cules or port ions thereof - for induc-

ing desired cell responses (Figure 3). For example, surface immobilization of adhesive peptides (specific por- tions of cell-adherent proteins) pro- motes subsequent cell at tachment to the pept ide-modif ied materials 6.

Growth factors, which generally tend to promote cellular proliferation and differentiation, can also be deposited on biomaterial surfaces to control cell/tissue responses such as bone format ion 7. There are cur rent ly a

number of research efforts focused on designing materials with reactive sur- face functional groups, and on refin-

ing strategies to reproducibly and

Materials Today 9

in of Mater ia ls for Biomedical E n g ee r i ng Applicat ic . . . . . . . . . .

All of the biomaterial modifications briefly described in this article funda- mentally operate at the level of the cell membrane, that is, on a subcellu- lar scale.The binding of specific mol- ecules to cellular receptors (i.e., pro- teins embedded in the cell mem- brane) initiates intracellular cascades of chemical signaling. These chemical cascades alter DNA replication and t ranscr ip t ion, and thus de te rmine how the cell responds to the bioma- terial modifications. Using self-assem- bled monolayers to control surface chemistry, investigators are beginning to elucidate the intraceUular signaling

pathways stimulated by interactions of cells wi th biomater ia ls 13. Unders tand ing the molecular- level mechanisms by which cells respond to extracellular, biomaterial-related stimuli is a necessary prerequisite to eventual ly modifying biomater ia l

properties at the molecular or atomic level, with the goal of controlling cell and tissue interactions with implant-

ed materials.

Conclusion

Future work on control l ing cell-bio- material interactions will focus on

cont inual ly smaller (microscopic to molecular to genetic) scales. Micro- EleetroMechanical Systems (MEMS) processes and nanotechnologies may yield exciting, breakthrough strate- gies and techniques which can be used to f ine-tune the surface proper- ties of traditional biomaterials which already possess desirable bulk prop- erties. New analytical methodologies will need to be developed in order to quantitatively confirm and character- ize these novel surface modifications, as well as the cell /biological respons- es to such modificat ions.The underly- ing force driving ne w developments in this area of materials research is the knowledge that rationally design- ing materials for specific biomedical

appl icat ions could provide signifi- cant clinical benefi ts to pat ients with a variety of medical problems.

Note: Many of the examples briefly

p resen ted in this overview were drawn from the full-length review arti- cles and research publications in a recent special issue of Biomate r ia l s

("Current Challenges in Cell- Biomaterial Interactions", volume 20, number 23/24, December 1999). The full papers for this issue can be obtained free-of-charge at: www.elsevi- er.com/locatye/biomaterials

1) M~ss~ A.J.~ Hamburger~ SÈ M~re~ R.M.~ J~ Jeng~ L L. and H~wie~ LJ. Use ~f se~ected medical device imp~ants in the United States~ ~ 988~ Nati~na~ Center f~r Health Statistics~ Hyattsvi~le~ MD. (1991).

2) Ka~W.J.Eva~uati~n~f~r~tein~m~du~atedmacr~phagebehavi~r~nbi~materials:designingbi~mimeticmateria~sf~rce~u~arengineering~Bi~materia~s~2~:2213-21.(~999).

3) Jenney, C.R. and Anderson, J.M. Alkylsilane-modified surfaces: inhibition of human macrophage adhesion and foreign body giant cell formation, J Biomed Mater Res, 46:11-21. (1999).

4) James, K., Levene, H., Parsons, J.R. and Kohn, J. Small changes in polymer chemistry have a large effect on the bone- implant interface: evaluation of a series of degradable tyrosine- derived polycarbonates in bone defects, Biomaterials, 20:2203-I2. (I999).

5) Brunette, D.M. and Chehroudi, B. The effects of the surface topography of micromachined titanium substrata on cell behavior in vitro and in vivo, J Biomech Eng, 121:49-57. (I999).

6) Mann, B.K., Tsai, A.T., Scott-Burden, T. and West, J.L. Modification of surfaces with cell adhesion peptides alters extracellular matrix deposition, Biomaterials, 20:2281-6. (1999).

7) Lind, M., Overgaard, S., Soballe, K., Nguyen, T., Ongpipattanakul, B. and Bunger, C. Transforming growth factor-beta 1 enhances bone healing to unloaded tricalcium phosphate coated implants: an experimental study in dogs, J Orthop Res, 14:343-50. (1996).

8) lto, Y. Surface micropatterning to regulate cell functions, Biomaterials, 20:2333-42. (1999).

9) Kam, L., Shain, W., Turner, J.N. and Bizios, R. Correlation of astroglial cell function on micro-patterned surfaces with specific geometric parameters, Biomaterials, 20:2343-50. (1999).

10) Lu, L., Kam, L., Hasenbein, M., Nyalakonda, K., Bizios, R., Gopferich, A., Young, J.F. and Mikos, A.G. Retinal pigment epithelial cell function on substrates with chemically micropat- terned surfaces, Biomaterials, 20:2351-61. (1999).

11) Kane, R.S., Takayama, S., Ostuni, E., Ingber, D.E. and Whitesides, G.M. Patterning proteins and cells using soft lithography, Biomaterials, 20:2363-76. (1999).

12) Kam, L. Modulation of neuron and astroglial cell function by micropatteming and immobilization of select biomolecules on biomaterial surfaces, Doctoral dissertation, Rensselaer Polytechnic institute, Troy, NY, USA. (1999).

13) McClary, K.B. and Grainger, D.W. RhoA-induced changes in fibroblasts cultured on organic monolayers, Biomaterials, 20:2435-46. (1999).

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