Biohybrid Limbs - RIMS

Volume 90 No. 1 January 2007

�Biohybrid LimbsA CME Issue

1VOLUME 90 NO. 1 JANUARY 2007

Medicine and Health/Rhode Island (USPS 464-820), a monthly publication, is owned and published by the Rhode Island Medical Society, 235Promenade St., Suite 500, Providence, RI 02908, Phone: (401) 331-3207. Single copies $5.00, individual subscriptions $50.00 per year, and $100per year for institutional subscriptions. Published articles represent opinions of the authors and do not necessarily reflect the official policy of the Rhode IslandMedical Society, unless clearly specified. Advertisements do not imply sponsorship or endorsement by the Rhode Island Medical Society. Periodicals postagepaid at Providence, Rhode Island. ISSN 1086-5462. POSTMASTER: Send address changes to Medicine and Health/Rhode Island, 235 Promenade St.,Suite 500, Providence, RI 02908. Classified Information: RI Medical Journal Marketing Department, P.O. Box 91055, Johnston, RI 02919,phone: (401) 383-4711, fax: (401) 383-4477, e-mail: [email protected]. Production/Layout Design: John Teehan, e-mail: [email protected].

UNDER THE JOINTEDITORIAL SPONSORSHIP OF:

Brown Medical SchoolEli Y. Adashi, MD, Dean of Medicine& Biological Science

Rhode Island Department of HealthDavid R. Gifford, MD, MPH, Director

Quality Partners of Rhode IslandRichard W. Besdine, MD, ChiefMedical Officer

Rhode Island Medical SocietyBarry W. Wall, MD, President

EDITORIAL STAFFJoseph H. Friedman, MD

Editor-in-ChiefJoan M. Retsinas, PhD

Managing EditorStanley M. Aronson, MD, MPH

Editor Emeritus

EDITORIAL BOARDStanley M. Aronson, MD, MPHJay S. Buechner, PhDJohn J. Cronan, MDJames P. Crowley, MDEdward R. Feller, MDJohn P. Fulton, PhDPeter A. Hollmann, MDSharon L. Marable, MD, MPHAnthony E. Mega, MDMarguerite A. Neill, MDFrank J. Schaberg, Jr., MDLawrence W. Vernaglia, JD, MPHNewell E. Warde, PhD

OFFICERSBarry W. Wall, MD

PresidentK. Nicholas Tsiongas, MD, MPH

President-ElectDiane R. Siedlecki, MD

Vice PresidentMargaret A. Sun, MD

SecretaryMark S. Ridlen, MD

TreasurerKathleen Fitzgerald, MD

Immediate Past President

DISTRICT & COUNTY PRESIDENTSGeoffrey R. Hamilton, MD

Bristol County Medical SocietyHerbert J. Brennan, DO

Kent County Medical SocietyRafael E. Padilla, MD

Pawtucket Medical AssociationPatrick J. Sweeney, MD, MPH, PhD

Providence Medical AssociationNitin S. Damle, MD

Washington County Medical SocietyJacques L. Bonnet-Eymard, MD

Woonsocket District Medical Society

RHODE ISLANDPUBLICATION OF THE RHODE ISLAND MEDICAL SOCIETY

Medicine � Health VOLUME 90 NO. 1 January 2007

COMMENTARIES

2 Dress Codes for DoctorsJoseph H. Friedman, MD

3 Perils of Life In the Left Lane

Stanley M. Aronson, MD

CONTRIBUTIONS

BIOHYBRID LIMBS: A CONTINUING MEDICAL EDUCATION ISSUEGuest Editor: Roy K. Aaron, MD

4 Biohybrid Limbs: New Materials and New PropertiesRoy K. Aaron, MD, and Jeffrey R. Morgan, PhD

6 Regenerative Medicine for Limb TraumaRoy K. Aaron, MD, Deborah McK. Ciombor, PhD, Michael Lysaght, PhD,

Edith Mathiowitz, PhD, and Michael G. Ehrlich, MD

10 Biomimetic Prostheses: The Next GenerationHugh Herr, PhD, and Samuel Au, MS

12 Neuromotor Prosthesis DevelopmentJohn P. Donoghue, PhD, Leigh R. Hochberg, MD, PhD, Arto V. Nurmikko, PhD,Michael J. Black, PhD, John D. Simeral, PhD, and Gerhard Friehs, MD

15 Identifying Clinically Meaningful Improvement in Rehabilitation ofLower-Limb Amputees

Linda Resnik, PhD, PT, OCS

21 Blast Injuries in Civilian PracticeChristopher T. Born, MD, FAAOS, FACS, Ryan Calfee, MD, and Joann Mead, MA

25 CME Questions

COLUMNS

27 GERIATRICS FOR THE PRACTICING PHYSICIAN – Using the Comprehensive ClinicalApproach to Older PatientsAna C. Tuya, MD, and Richard W. Besdine, MD

29 HEALTH BY NUMBERS – Birth Defects in Rhode IslandSamara Viner-Brown, MS, and Meredith Bergey, MSc, MPH

32 PHYSICIAN’S LEXICON – A Nervous Assortment of WordsStanley M. Aronson, MD

32 Vital Statistics

34 January Heritage

35 2006 IndexCover: “Envisioning Future Prosthetics,” 3Ddigital art, by Bryan Christie, an award-winningillustrator who has worked for Newsweek, TheNew York Times, Esquire, Wired, and NationalGeographic. He began as an assistant art directorat Scientific American Magazine, where he de-signed and illustrated covers and editorial con-tent. While there, Bryan was impressed by thedistinctive aesthetic of the magazine from the50s and 60s. His art strives to represent ideas,not just objects. Illustrating the unseeable is hisspecialty. Web site: bryanchristiedesign.com

2MEDICINE & HEALTH/RHODE ISLAND

Dress Codes for Doctors�

Commentaries

THERE ARE TWO PARTS TO THIS COLUMN.The first is my reflection on dress codes,and the second is my reflection on some-one else’s reflection on dress codes.

My medical school training empha-sized a strict dress and behavior code. Nei-ther students nor doctors were allowedto drink beverages or eat in front of pa-tients. All adult patients were called Mr.,Miss or Mrs. (before Ms was coined).Medical students and house-officers al-ways wore white coats. Men wore ties.Coats and ties were required regardlessof the temperature. At that time the hos-pitals were not air-conditioned so that thewards in Manhattan during the summerswere hot and uncomfortable. And theend rooms on most wards were large, with12 beds. It was not pleasant. InterestinglyI didn’t rebel. I always wear a tie when Isee patients (except on weekends). I feeluncomfortable if a medical student orresident working with me is not wearinga tie and a white jacket. It has been im-printed on me that this dress is a token ofrespect, not for the profession, but for thepatient. It’s true that I don’t always wearmy white coat. I usually do, but in myprivate office, with my bald head, graytemples and gray beard, I can compen-sate somewhat by the “gravitas” of age.But my students can’t.

During my training I rotatedthrough city hospitals. It was there that Ibelieve the dress code should have beenenforced the most, and was actually fol-lowed the least. It is in these bastions ofthe poor and the oppressed where thepatient needs to be treated with the re-spect they desire, not the dress down atti-tude that suggests social identification.The casual attire that is meant to indi-cate unity with the oppressed, that dresscodes don’t matter, that we’re all in thistogether and are all equal, actually areoften interpreted as a sign that “real”doctors, like the ones on TV catering torich people, don’t work at the city hospi-

tals, that these hospitals are for traineeswho aren’t good enough for the volun-tary hospitals and they reflect their poorquality with their insensitivity by “dress-ing down.”

This isn’t a problem in Rhode Islandas it is in the big cities. But a more chal-lenging problem that I have noticed, al-beit rarely, is the female student whodresses in a manner I deem thoughtless.In fact, the only house-officer whosedress I’ve ever complained about wasmale. I found him making rounds on aweekend wearing blue jeans and a t-shirt.I talked to his chair who threw up hishands and said he’d already talked to theyoung man and there wasn’t anything hecould do. After all, it didn’t make senseto threaten to remove him from the pro-gram for determined minor social mal-adjustment. A second dress problem Iheard about, was a neurology attendingmany years ago who refused to wear a tieor white coat, and kept his shirt unbut-toned, exposing his hairy chest. The chairof another department told him he wasforbidden from entering his wards to seepatients there, even to recruit them forhis studies, unless he dressed better. Theneurologist chose to not change. Hedoesn’t work in RI any more.

The New York Times ran a columnrecently, written by a woman physician,describing the conflict she felt when amale colleague asked her to talk to a fe-male house-officer about her mini-skirtand low blouse. The male physician wasastute enough to realize that he shouldn’tbe talking to the resident himself, but thefemale colleague was herself very uncom-fortable about confronting the resident,and, in fact, chose not to do it. I was sym-pathetic to them both. I had had the sameproblem with a student. In my case, luck-ily, it was a high school student doing aresearch project. She was so young that Iwas able to inform her about my dresscode without causing a problem. If she

had been a medical student or house-of-ficer, I wasn’t sure how’d I handle it. Theproblem gave me pause. I thought I’dprobably ask some older female profes-sional to talk to the involved student, justas the N Y Times article described.

So, imagine my surprise at Thanks-giving, when my medical student daugh-ter announced her letter to the NY Timesdecrying the bigotry of the very articleabout dress codes that I had identifiedwith so closely (both the article and thedress codes). Luckily for me she declaimedbefore I did, so I knew where to stow myopinion. I marveled both at how differ-ent the two ends of the gender and agespectrum looked at things, and at howsmart and independent a thinker mydaughter had become. (She never readswhat I write so my comments are safehere).

I am therefore stuck with a dilemma.My training, my hard wired inner core,tells me that male medical students shouldwear clean white jackets and ties and beeither clean shaven or bearded but notin-between and women should dress rela-tively modestly. On the other hand, mydemurely dressing daughter tells theworld, “break out the defibrillators” be-cause women doctors can’t be told howto dress, and if they want to wear miniskirts and bear their midriff, they won’tbe stopped.

I know now that I, at least, won’t bestopping them.

– JOSEPH H. FRIEDMAN, MD


Perils of Life In the Left Lane�

WHAT DO MICHELANGELO, MARTINA NAVRATILOVA AND MARILYNMONROE HAVE IN COMMON? Certainly enduring fame and thefact that they all possess given names beginning with the letterM. But further, all three are left-handed, a biological character-istic that they share with about 10% of the human population.

It should not come as a surprise, then, if about one-tenth ofthe world’s famous folk are left-handed. The critical questionreally is whether left-handedness is merely a bland, neutral at-tribute or alternatively, whether it confers measurable qualities –strengths or weaknesses, abilities or vulnerabilities, positive ornegative properties—upon those endowed with this characteric?

The most obvious of the many positive biological traits islongevity, the ability to live longer than others in the same eraand the same community. By this criterion it appears that theright-handed live longer. About 10% of the total population is,on average, left-handed, although this frequency diminishes pro-gressively with age. Thus, about 13% of youngsters are left-handed but beyond the age of 80 this percent drops to about1%. Lefthanders, as many emergency rooms will inform you,are more prone to accidents [both industrial and vehicular], pos-sibly because they live in a world where most tools and kitchencontrivances are designed for right-handers. Researchers havealso noted that autoimmune diseases and various psychoneuro-ses seem to be more common in lefthanders. On the other hand,lefthanders seem to recover more readily from the disabling ef-fects of stroke and are less prone to become aphasic followingbrain damage.

These biological factors favoring right-handers pale to in-significance when compared with the cultural prejudice againstleft-handedness. Consider the semantics of the words left andright. In English, the word right signifies correctness [the rightthing to do], laudable stature [uprightness], ethical correctness[knowing right from wrong], inalienable entitlements [Bill ofRights], inherited privileges [birthrights], rationality [he’s not inhis right mind], legitimacy [the divine right of kings] as well asfactualness, accuracy, dexterity [from the Latin, dexter, meaningon the right hand] and adroitness [from the French, meaningon the right]. Left, on the other hand [Ah, but which hand?]usually connotes clumsiness, awkwardness, lameness, out of step[left-footed], tardiness [left behind], something twisted [a left-handed compliment] or evilness [the Latin word for left is sinis-ter].

Thus there are both biological advantages and disadvan-tages to being left-handed; but in a world mildly hostile to left-handers [in some cultures where left-handedness is a satanic sign,left-handed children are routinely punished], the right-handedmajority manages to survive somewhat longer.

With the odds slightly against them, how have the leftiesprospered in this competitive world? Until James Garfield waselected in 1880, no American president had been left-handed.Since 1928, however, six of the 13 presidents [46%] have beensouthpaws [Hoover, Truman, Ford, Reagan, G.H.W. Bush andClinton]. Perhaps, in a world of increasing chaos, so much veer-ing toward left-field, that this nation turns to those lefties who

see things differently [an anonymous observer declared that leftiesperceive the right-handed world as though viewed through amirror]. Two of the current nine Justices of the Supreme Court[Kennedy and Ginsburg], incidentally, are also left-handed.

Many world leaders of the past have been said to be left-handed, especially those who excelled in military conquest. Thesefamous southpaw chieftains included Alexander the Great, JuliusCaesar, Tiberius, Charlemagne, Napoleon Bonaparte, FidelCastro and even Joan of Arc and Queen Victoria of England.The bolt-action military rifles of the past, incidentally, were de-signed solely for right-handed infantry. Did these biased weap-ons make the left-handed, left-eyed, foot soldiers poorer snip-ers?

Left-handedness seems to dominate the contributors to twoforms of the graphic arts: architecture and painting. Left-handedartists of the past have included Leonardo da Vinci,Michelangelo, Raphael, Albrecht Durer, Hans Holbein, M.C.Escher, and Paul Klee. The incidence of left-handedness amongstteachers in institutions of higher education and professionalmusicians is also significantly higher than in the general popula-tion [although none of the virtuoso violinists of the past centurywere lefties since the instrument is designed only for right-handedmusicians. Yet some of the leading guitarists—also an instru-ment designed for right-handed musicians—were southpaws,including Paul Simon, Eric Gale and Albert King.]

Left-handed athletes have excelled in most sports exceptfor professional boxing [although “Gentleman” Jim Corbett wasa southpaw]. In addition there has been a conspicuous absenceof great golfers who are left-handed. In tennis, however, beingleft-handed is sometimes considered an advantage over oppo-nents who customarily play only against other right-handed play-ers. Quite a number of the recent tennis champions have beensouthpaws [Connors, Laver, McEnroe, Vilas, Navratilova andSeles].

Are there other asymmetries regarding handedness? A re-cent study conducted by Christopher S. Roebuck, a professorof economics at Lafayette College in Pennsylvania concludedthat “college-educated left-handed men earn almost 15% more,on average, than right-handed men with similar educations.”The study, a kind of left-handed vindication for the southpaws,made no mention of whether such an economic advantage per-tained also to left-handed women.

More studies are clearly needed to determine the competi-tive status of the lefties in a biased world. Until then, these left-handed survivors must display a fragile bravado, celebrate a dayof their own [August 13, International Lefthanders Day] andresort to valiant bumper stickers such as: “We are all born right-handed. Some of us, however, have overcome this handicap.”

– STANLEY M. ARONSON, MD


Biohybrid Limbs: New Materials and New PropertiesRoy K. Aaron, MD, and Jeffrey R. Morgan, PhD

�BIOHYBRID STRUCTURES ARE COMPOSED OFboth biological tissue and non-biologicalcomponents. An example in current clini-cal use is the uncemented joint replace-ment, in which metal implants are inte-grated into bone. The resultingbiocomposite, or biohybrid, has uniquemechanical properties. In addition to or-thopaedic endoprostheses (bone and jointreplacements), current examples of success-ful biohybrids include growth factor aug-mented skeletal repair and engineered skin,cardiovascular grafts, and neuro-prosthet-ics. Other biohybrid structures in develop-ment include secretory cells embedded inimplantable scaffolds, and a number ofdrug delivery systems and sensors.

The biohybrid limb is conceptualizedas consisting of biological tissues and non-biological materials as endo- or exo- pros-theses. Theoretically, a biohybrid limb canbe constructed to improve function aftertraumatic tissue loss or therapeutic ablation.Conceptualizing a limb as a biohybrid or-gan frees the researcher and clinician fromconstraints imposed by the limitations ofbiological tissue or biomaterials, respectively.Biohybrid limb research integrates inde-pendent developments in regenerativemedicine, neurotechnology, orthopedics,and robotic prostheses, to maximize limbfunction. The biohybrid vision includes op-timized interfaces with, and control of, tech-nologically advanced biomimetic prosthe-ses.

Many of these concepts are expandedupon in the accompanying articles withinthis volume. Moreover, the following ar-ticles will illuminate an important aspect ofbiohybridity—these structures often pos-sess new physical and physiological prop-erties that require full understanding be-fore they can be most effectively utilized inthe clinical setting. Biophysical propertiesresult from the interface between prosthet-ics and biological tissues. In the case of bone,a variety of textured or coated surfaces havebeen created to encourage bone to growinto and interdigitate with the prosthetic.These coatings create optimal porosity andcan be supplemented by chemical adju-vants, such as hydroxyapatite. (Figure 1)

Here, we will present one example ofa novel biohybrid structure—osseointegrated transcutaneous implants—that have the potential to create an improvedinterface between a residual limb after am-putation and a biomimetic prosthetic limb.

Fixation of prostheses to residual limbsis currently achieved through plastic sock-ets that fit around the end of the limb.These devices are often uncomfortable, hot,and irritating to the skin—especially totraumatized and scarred skin. Moreover,scar and poor socket fit often lead to skinulceration, infection and pain, all of whichlimit the use of prosthetic limbs. In fact,chronic pain, with or without skin break-down, causes 25% - 35% of lower extrem-ity amputees to abandon their prosthetic

limbs and ambulation.The technique of osseointegration is a

promising method of fixing a prosthesis di-rectly to bone, which has the potential toby-pass some of these problems. This tech-nique integrates a titanium implant withbone, much like hip replacements; how-ever, the implant extends from the bone toexit through the skin, creating an anchorfor the prosthetic limb. (Figure 2) Thismethod bypasses skin contact with the pros-thesis, reducing pain.

In true osseointegration, the livingbone becomes fused with the oxide layer ofthe titanium and this anchorage persistsunder normal conditions of weight bear-ing. This allows osseo-perception, i.e., theability of patients with osseointegrated de-vices to identify tactile thresholds transmit-ted through their prostheses. Through in-creased osseo-perception, the biohybridlimb has the potential to improve amputeeperception of his or her environment. Sev-eral fully internal osseointegrated deviceshave been described for orthopaedic ap-plications, including metacarpal-phalangealjoints.1 Indeed, titanium joint replace-ments in use worldwide incorporateosseointegration principles.

The application of these principles toamputees, however, has raised concerns be-cause the titanium device is transcutaneous.Concerns have been raised not so muchabout the integration of the device withbone, but about the development of path-

Biophysical properties result from the interface between prosthetics and biological tissues. In the case of bone, a variety of textured orcoated surfaces have been created to encourage bone to grow into and interdigitate with the prosthetic. These coatings create optimalporosity and can be supplemented by chemical adjuvants, such as hydroxyapatite. Each treatment creates different physical conditions,encouraging in-growth of soft or hard tissues.

Image courtesy of J.Dennis Bobyn, Ph.D., Jo Miller Orthopaedic Research Laboratory, Montreal General Hospital, McGill University.

Figure 1: Scanning electron micrographs of textured or coated metallic implant surfaces


ways around the implant through soft tis-sues where environmental contaminationcould cause titanium corrosion and boneinfection. This could lead to further loss ofbone, resulting in an even shorter residuallimb, and thus even greater problems inaffixing a prosthesis. Clinical reports onosseointegration are scanty and do not ad-dress questions of transcutaneous compli-cations. However, anecdotal reports do de-scribe infections and prosthesis loosening.

These complications may be due to alack of soft tissue integration with the tita-nium implant, and the absence of a bar-rier between the internal and external en-vironments. Percutaneous devices thatpenetrate the skin are widely used in a va-riety of other clinical applications, includ-ing peritoneal dialysis, indwelling cath-eters, and dental implants.1,2 Each ofthese applications suffers from similar com-plications related to the effectiveness withwhich skin seals around the implant. Sev-eral distinct failure modes that limit long-term usefulness of these devices have beenidentified, including marsupialization,permigration, infection and abscess forma-tion, and avulsion.3 While it is true thatthe dermal response is critical for the at-

tachment of the skin and that it providesthe bulk of the skin’s mechanical attach-ment to the device, it is also well knownthat undesirable responses to percutane-ous devices are common. Moreover, sub-optimal attachment in the epidermis mayinfluence events in the dermis. In recentyears, it has become increasingly clear thatcytokines and growth factors secreted fromthe epidermis, notably interleukin-1 (IL-1), influence cellular events in the dermisand vice versa. Significant quantities ofIL-1 are released when keratinocytes arestretched.4 Thus, suboptimal attachmentof the epidermis may increase inflamma-tion and affect the maturity of the con-nective tissue formed by the dermis. Con-cerns about infection and loosening, andconsequent loss of bone in residual limbs,have focused our attention on the inter-face of soft tissue—particularly skin—with osseointegrated prosthetics. Our re-search goal is to develop an environmen-tal seal by integrating skin and dermis withtitanium, thus eliminating contact be-tween the bone and the environment andrestricting contamination of the prosthe-sis and bone.

Most osseointegration devices aremade of titanium because of its strength,ductility, low density, and corrosion resis-tance.5,6 The good corrosion resistance oftitanium is the result of a strongly adherentoxide surface film.7,8,9 The electrochemis-try of titanium is such that, in the presenceof oxygen, this film is rapidly repaired evenif it is ruptured. However, hydrogen, be-cause of its small atomic size, can penetratethe oxide, enter the titanium, and react withthe metal to form hydrides which are verybrittle, destroy the mechanical propertiesof the titanium and lead to materials frac-ture.7,8

Thus, conditions of low pH can lead totitanium failure. The most common mecha-nism of breakdown of the oxide film is crev-ice corrosion.5,6 The metal may initially becovered with an oxide, but very slowly cor-rosion occurs and, as the metal is oxidized,the oxygen in the solution is consumed.These reactions can lead to the establishmentof acidic conditions in the crevice, resultingin rapid corrosion of the metal. It is indeedwell known that occluded biological solu-tions can be particularly corrosive becauseof the concentrations of inflammatory cellsand their products, and the presence of acidicpH with high hydrogen content.

One way to avoid corrosion at the siteof the implant is to locate cell growth di-rectly onto the surface of the titanium.From the materials point of view, we areexploring two primary ways in which onecould effect cell attachment—either bychanging the composition and microstruc-ture of the alloy, or by changing the mor-phology of the surface. To improve the softtissue interface with osseointegrated pros-theses, we are (1) determining the optimalsurface chemistry and morphology of tita-nium for the attachment of epidermalkeratinocytes and dermal fibroblasts, and(2) developing a finite element analysismodel to understand the mechanics of theskin-prosthesis interface that will be usedto improve device design.

One approach will be to treat the sur-face of the titanium in various ways in orderto provide a porous surface that might en-hance cell adhesion. One possible methodis anodization of the titanium to produce aporous oxide, coating the surface with pow-der that could be sintered to different de-grees of porosity. Another is the use of vari-ous mechanical surface-roughening treat-ments. We have devised a novel method torapidly produce thin films of titanium andits alloys with which we can control the chem-istry, grain size, and morphology of the metalsurface. Experiments are underway to de-termine the stability of these surfaces underin vitro physiological conditions. We havealso started initial testing of these surfaces andhave set up quantitative fluorescent assays tomeasure cell number, cell adhesion, and cellmorphology. These approaches will facili-tate the rapid and quantitative screening ofa large array of surface chemistries and mor-phologies to identify those optimal for cellattachment.

REFERENCES1. Brånemark R, Brånemark, PI, et al. Osseointegration

in skeletal reconstruction and rehabilitation. J RehabRes Develop 2001; 38: 175-81.

2. Paquay YCGJ, et al. Tissue reaction to Dacronâvelour and titanium fibre mesh used for anchor-age of percutaneous devices. Biomaterials1996;17: 1251-6.

3. Von Recum AF. Applications and failure modes ofpercutaneous devices. J Biomed Materials Res 1984;18: 323-36.

4. Murphy JE, Robert C, Kupper TS. Interleukin-1and cutaneous inflammation. J Invest Dermatol2000; 114: 602-8.

5. Wagoner-Johnson AJ, Bull CW, et al. The influenceof microstructure and strain rate on compressive de-formation behavior of Ti-6Al-4V. Metall Mater Trans.A 2003; 34A: 295.

A transcutaneous titanium rod is affixedto the bone of the residual limb andprotrudes from the skin. The exoprothesisis attached to the protruding rod, by-passing contact with the skin.

Figure 2: Lower-limbprosthetic, fixed to the femur


Regenerative Medicine for Limb TraumaRoy K. Aaron, MD, Deborah McK. Ciombor, PhD, Michael Lysaght, PhD, Edith Mathiowitz, PhD,

and Michael G. Ehrlich, MD

REGENERATIVE MEDICINE—THE ENGINEERINGOF TISSUE OR ORGAN REPLACEMENTS—is one solution to an entire spectrum ofdiseases, including the focus of our re-search, tissue loss following limb traumaand traumatic amputation.

CELL BASED THERAPIES FORTISSUE REGENERATION

Because many of the same signalingmolecules that regulate cartilage develop-ment in embryogenesis are re-expressedin post-natal life during growth and re-pair, many investigators have taken a de-velopmental approach to understandingand promoting cell growth and repair, inwhich connective tissue repair in post-na-tal life is studied as a recapitulation, at leastin part, of early cell developmental path-ways. In these early stages of development,competent cells are exposed to growth fac-tors. In response, they can proliferate ordifferentiate, often creating complex tis-sues and organs.1 This provides the theo-retical basis for using growth factors tostimulate endogenous repair and to facili-tate cell-mediated engineered repair.

Tissue regeneration involves the re-expression or re-induction of genes thatregulate development.2,3 Tissue engineer-ing research will mostly likely require anincreasingly complex understanding ofthe regulatory effects of endogenous physi-cal and chemical gradients on progenitorcells and synthesis of extracellular matrix.Our observations have suggested a strat-

�egy of introducing growth factors to re-pair bone or cell-based engineered con-structs in order to stimulate proliferationand/or differentiation of progenitor cells.(Figure 1) While some success has beenachieved by injecting single growth fac-tors into skeletal defects, this strategy hasbeen limited by problems of dosing re-lated to pharmacokinetics that can resultin loss of growth factors from the desiredsite by diffusion or inactivation, as well asan inability to sustain delivery.

SYNOVIAL CELLS FOR CARTILAGEREGENERATION

The membrane lining the synovialjoint produces synovial fluid. It is particu-larly relevant to explore the tissue gener-ating properties of synovial tissue becauseof its ready availability to the surgeon op-erating on joints. In addition, it has a dem-

onstrated propensity to undergo chondro-genesis.

Since synovium contains a mixedpopulation of cells that respond differentlyto various growth factors, we first had toachieve isolation of separate synovial celltypes with magnetic bead separation. Earlyin our research, we succeeded in isolatinga progenitor cell population with strongpredilection for chondrogenic differentia-tion. We then exposed this population tospecific growth factors and signaling mol-ecules involved in chondrogenesis: FGF-2, TGF-β

1, and IGF-1. Each represents

different classes of growth factors withdocumented effects on stem cells andchondrocytes. FGF-2 is a mitogen; TGF-β

1 stimulates differentiation; and IGF-1

promotes extracellular matrix secretion.In order to maximize chondrogenesis,

we studied high density synovial pellets in-

Figure 1: Fabricating a cartilage biocomposite

The cartilage biocomposite pictured above (right) has been fabricated fromprogenitor cells, growth factors, and a scaffold.

6. Wagoner Johnson AJ, et al. Deformation mecha-nisms in Ti-6Al-4V/TiC composites Metall MaterTrans A 2003; 34A: 1869.

7. Briant CL, Wang ZF, Chollocoop N. Hydrogenembrittlement of commercial purity titanium. Cor-rosion Science 2002; 44: 1875.

8. Wang ZF, Briant CL, Kumar KS. Hydrogenembrittlement of grade 2 and grade 3 titanium in a6% NaCl solution. Corrosion 1998; 54: 553.

9. Wang ZF, Briant CL, Kumar KS. Electrochemical,galvanic, and mechanical response of grade 2 yitaniumin 6% NaCl solution. Corrosion 1999; 55:128.

Roy K. Aaron, MD, is Professor of Or-thopaedic Surgery at Brown Medical School,and Director of the VA Center for Restorativeand Regenerative Medicine.

Jeffrey R. Morgan, PhD, is Associate Pro-fessor of Medical Science and Director of theGraduate Program in Biomedical Engineer-ing and Department of Molecular Pharma-cology, Physiology and Biotechnology atBrown Medical School.

ACKNOWLEDGEMENTSFunding for this research comes from

the Veterans Affairs Rehabilitation Researchand Development Center for Excellencegrant establishing the Center for Restorativeand Regenerative Medicine, which is affili-ated with the Providence VA Medical Cen-ter, Brown University, and MIT.

Portions of this report have appearedin abbreviated form in the JAAOS, Vol 14,No. 10, pp. S198+.

CORRESPONDENCERoy K. Aaron, MDBrown Medical School100 Butler DriveProvidence, RI 02906Phone: (401) 444-4485e-mail: [email protected]


cubated with FGF-2 and IFG-1, alone orin combination with TGF-β1. Our resultssuggest that (1) FGF-2 supplementationincreased the cell number of synoviocytes;(2) TGF-β1 stimulated chondrogenic dif-ferentiation in a dose-dependent manner;(3) IGF-1, combined with TGF-β1, candramatically improve chondrogenesiscompared to the supplementation of TGF-β1 alone, and this improvement is bothtime- and dose- dependent. These resultsdemonstrated, for the first time to ourknowledge, the TGF-β1-dependent chon-drogenic effect of IGF-1 and FGF-2 onsynovial fibroblasts and the optimizationof chondrogenesis by the sequential ap-plication of growth factors.

POLYMER ENCAPSULATED DELIVERYOF GROWTH FACTORS FOR TISSUEENGINEERING

Growth factors and cytokines are pro-teins involved in cell growth, repair anddifferentiation. One promising approachto the problem of growth factor deliveryis encapsulation of growth factors in nano-or microspheres, which release cytokinesover time.4 In principle, several encapsu-lated growth factors could be deliveredwithin physiological dosing conditions toa repair site, or included in cell-based en-gineered constructs in order to providesequential or complementary release ofgrowth factors that could act in a con-certed fashion to optimize tissue repair.The kinetics of release may be either con-stant or cyclic over time, or triggered byan external physical force (e.g., ultrasoundor pulsed electromagnetic fields).5,6 Poly-mer microspheres have been fabricated inour laboratory in the size range of 0.1-10mm and have been used to encapsulate

and release a wide variety of bioactive mol-ecules while maintaining greater than90% bioactivity. (Figure 2) In particularthey have been used to successfully encap-sulate and release active growth factors andcytokines such as insulin, IL-2, IL-12, andgrowth hormone. To date, we haveachieved encapsulation of FGF2 andTGF-β1. As part of our research in en-capsulating TGF-β1, and release kineticsof TGF-β1 are being determined.

We have also developed microsphereformulations that can deliver growth fac-tors following a latency period. This facili-tates the sequential application of growthfactors, particularly IGF-1, that is impor-tant in cartilage regeneration. In particu-lar, we have encapsulated IGF-1 in PLGAmicrospheres and showed active IGF-1release over 80 days. By incorporatingbovine serum albumin in the formulations,we were able to nearly eliminate the ini-tial burst of IGF-1. (Figure 3a and 3b)

Furthermore, we created three-di-mensional scaffolds from growth-factor-loaded microspheres using a unique va-por fusion technique. By controlling the

fusion parameters (i.e., time, amount ofvapor, microsphere composition), we cancreate scaffolds of various shapes, sizes, andporosities that can release proteins underpreprogrammed conditions. Such con-structs may be useful for cell delivery incartilage and other tissue engineering ap-plications.

Immunoisolated cell therapy repre-sents an alternative approach to deliveryof growth factors and cytokines.7 In thisapproach, cells that are genetically modi-fied to constitutively release TGF-β

1 in

both the active and latent form are en-capsulated within a semi-permeable bar-rier (biodegradable polymer capsules) andimplanted in a host. (Figure 4) Bioactivesubstances, e.g., TGF-β

1 or FGF2, then

diffuse from the capsule. Using availabletechniques for creating capsules and mea-suring and controlling their performance,in vitro release profiles from microencap-sulated genetically modified living cellshave been measured and optimized. NIH3T3 murine fibroblasts have been geneti-cally modified to synthesize and secretehuman TGF-β

1 and have been encapsu-

lated in microspheres. The approach ishighly appealing because released growthfactors are freshly produced and biologi-cally active. Moreover, release rates are con-stant in time without the detrimental“starburst” effect.

Our group has also developed andcharacterized in vitro and in vivo a familyof microcapsule delivery vehicles compris-ing Ca2+-alginate-coated fibroblasts geneti-cally modified to constitutively release TGF-β

1. No evidence of adverse host reaction

was identified. Overall, the data suggeststhat these novel capsules are suitable forevaluation as sources of TGF-β

1 in applica-

tions such as bioartificial cartilage.

Figure 2: Polymer beads

Polymer beads are constructed from polylactic or polyglycolic acid and arebiodegradable to CO2 and water. Porosity can be controlled and, in turn, canregulate the release of growth factors.

Figure 3: IGF-1 Release

Fig. 3a: Release of IGF-1:Standard Microsphere

Fig. 3b: Delayed Release IGF-1demonstrating that the growth

factor does not appear until day10 of culture.


TISSUE ENGINEERING SOLUTIONSFOR BONE LENGTHENING

A serious problem for amputees isshort residual limbs, which are particularlycommon after traumatic amputations.When the residual limb is too short, a higherfunctional amputation level is required forprosthesis use. For example, short residualproximal tibias may not allow fitting with abelow-knee prosthesis and may require ex-tension of the prosthesis to the thigh, forc-ing the user to function as an above-kneeamputee. Similar problems exist in the up-per extremity for both above-elbow and be-low-elbow prostheses. Often, the higherfunctional amputation requires a heavier,and thus more awkward, proximal prosthe-ses, which in turn increases the energy costof movement. Proximal transfemoral am-putations can adversely affect sitting bal-ance and may require functional hip disar-ticulation prostheses.

One strategy is to lengthen the shortresidual limb (without bone grafting) byproducing new bone between vascularbone surfaces created by an osteotomyand separated by gradual distraction.8

(Figure 5) This process is called distrac-tion osteogenesis. A related operation, bonetransport, refers to the movement of a seg-ment of bone within the limb. A majorbenefit of limb lengthening with distrac-tion osteogenesis and bone transport isthat these techniques can convert a proxi-mal level of amputation to a more distalone. Bone transport techniques havebeen used to convert the level of ampu-tation, in one case, from hip disarticula-tion to above-knee, with gain in lengthof 9 cm.9

Limb lengthening with external fixa-tion is not new. These methods have beenused to generate bone to bridge interca-lary bone defects, correct deformities, andtreat bone loss secondary to tumor, in-fection, and trauma. The first reports ofbone lengthening for purposes of length-ening the limb were reported in the early1900s. The rate of lengthening is criticalboth to ensure bone healing and to mini-mize soft tissue complications, includingskin necrosis and neuropraxia. Tech-niques used to accomplish distraction os-teogenesis include external fixation withmonolateral half-pin frames, ring exter-nal fixation with wires under tension(Ilizarov technique), and lengtheningover intramedullary nails. Good resultshave been obtained with all techniques;choosing among them often dependsupon the extent of angulatory or rotarydeformities.

Stability of the fixation construct iscritical since unstable constructs can leadto premature consolidation or nonunion.Other problems that have been encoun-tered are long consolidation times, pin in-fections, inadequate skin coverage, and jointstiffness. Issues that may be related to thesecomplications, and that therefore may per-mit reduction in their frequency, are vas-cularity and tissue oxygenation, nutritionalstatus, and immunocompromise.

Tissue engineering strategies hold thepromise of accelerating the rate of elon-gation, maximizing the length of regener-ated bone, and diminishing osteoporosisand refracture. Some of these techniquesinclude the use of biomimetic scaffolds,growth factors, demineralized bone ma-trix, gene therapy, and interaction withphysical stimuli, including mechanical,ultrasound, and electrical.

While the biology of distraction os-teogenesis has been fairly well explored,no paradigm exists for augmented distrac-tion. Therefore we are examining the ef-fects of growth factors and physical stimulion vascularization and the synthesis of car-tilage and bone extracellular matrix usingbiological, radiographic, and biomechani-cal measurements of consolidation with anumber of lengthening rates.

One complication that can directlyaffect rehabilitation and the restoration oflimb function is delayed bone union afterlengthening. Our investigations have thusfocused on augmenting consolidation.One method for optimizing consolidationand healing of the lengthened segmentinvolves progressive weight-bearing. Ourstudies have collectively demonstrated thatmatrix formation and calcification oc-curred earlier in animals with distractionosteogenesis that were permitted gradedweight-bearing, compared to non-weight-bearing animals.10,11 Weight bearing hasalso been shown to stimulate new bloodvessel formation during distraction osteo-genesis. This suggests that early regener-ate bone is augmented by mechanical load-ing and supports the concept of earlyweight-bearing after limb lengthening.

Another potentially effective approachto optimizing bone consolidation involveslow intensity ultrasound stimulation.12 Ra-diographically, healing of the ultrasound-treated bones preceded that of the controlby approximately one week. The bone vol-ume fraction was significantly higher in the

Figure 4: Cells encapsulated in polymer beads

Cells are immobilized within polymer microcapsules. Cells can be transfectedwith one of several genes to function as producers of proteins such as growthfactors.

Tissue engineeringstrategies hold the

promise ofaccelerating the

rate of elongation,maximizing the

length ofregenerated bone,

and diminishingosteoporosis and

refracture.


ultrasound-treated animals. The ultra-sound-treated femurs were 20% stiffer and33% stronger than the control femurs.

Bioactive peptides can be used tostimulate healing after distraction osteo-genesis. Platelet-derived growth factor(PDGF) was discovered in 1974, follow-ing the observation that material releasedfrom platelets during clotting was capableof promoting the growth of various typesof cells. PDGF was subsequently purifiedfrom platelets, but it is now known to beproduced by a number of cell types, andit has also been found to be a mitogen foralmost all mesenchymally derived cells(blood, muscle, bone/cartilage, and con-nective tissue).

To date, we have manufactured newfixators for distraction in the rat (i.e., sur-gical units that hold the bone in a fixedposition after the surgery to separate thetwo ends of the bone being lengthened).We have also developed instruments toposition and tighten these fixators. In ad-dition, we have developed a collagen for-mulation that would gel almost immedi-ately upon hitting body temperature,which would prevent the PDGF fromflowing out from the interstices of theminimally distracted bone. Moreover, wehave begun developing a bioassay to evalu-ate the activity of the released PDGF fromour collagen gel utilizing the mitotic ef-fect on fibroblasts. Some of our prelimi-nary work using multiple injections lookspromising in terms of early healing.

REFERENCES1. Zaleske, DJ. Overview of musculoskeletal devel-

opment, in Skeletal Growth and Development:Clinical Issues and Basic Science Advances,Buckwalter JA et al., Editors. AAOS: Rosemont,IL, 1998: 5-16.

2. Helms JA, Le AX, Iwasaki M, The role of hedge-hog genes in skeletogenesis and repair, in SkeletalGrowth and Development: Clinical Issues and Ba-sic Science Advances,. Buckwalter JA, et al., Edi-tors. AAOS: Rosemont, IL, 1998: 131-46.

3. Vortkamp A, et al. Recapitulation of signals regu-lating embryonic bone formation during postna-tal growth and in fracture repair. Mechanisms ofDevelopment 1998; 71: 65-76.

4. Johnson O, et al. A month long effect from asingle injection of microencapsulated humangrowth hormone. Nature Med 1996; 3: 795-9.

5. Edelman ER, et al. Controlled and modulatedrelease of basic fibroblast growth factor.Biomaterials 1991; 12: 619-26.

6. Mathiowitz E, et al. Biologically erodablemicrospheres as potential oral drug delivery sys-tems. Nature 1997; 386: 410-4.

7. Lysaght MJ, Aebischer P. Encapsulated cells astherapy. Scientific American 1999; April: 77-84.

8. Aronson J. Limb-lengthening, skeletal reconstruc-tion, and bone transport with the Ilizaroz method,J Bone Joint Surg 1997; 79-A, 1243-59.

9. Park HW, Jahng JS., et al. Lengthening of anamputation stump by the Ilizarov technique. IntOrthop 1997; 21: 274-6.

10. Radomisli TE, Moore DC, et al. Weight-bearingalters the expression of collagen typed I and II,BMP 2/4 and osteocalcin in the early stages ofdistraction osteogenesis. J Orthopaedic Res 2001;19: 1049-56.

11. Pacicca DM, Moore DC, et al. Physiologic weight-bearing and consolidation of new bone in a ratmodel of distraction osteogenesis. J Ped Ortho-paedics 2002; 22: 652-9.

12. Eberson CP, Hogan KA, et al. Effect of low-intensity ultrasound stimulation on consolidationof the regenerate zone in a rat model of distrac-tion osteogenesis. J Ped Orthopaedics 2003; 23:46-51.

Roy K. Aaron, MD, is Professor of Or-thopaedic Surgery at Brown MedicalSchool, and Director of the VA Center forRestorative and Regenerative Medicine.

Deborah McK. Ciombor, PhD, is As-sociate Professor of Orthopaedic Surgery atBrown Medical School, and Associate Di-rector of the VA Center for Restorative andRegenerative Medicine.

Michael Lysaght, PhD, is Professor ofMedical Science (Research) and Engineer-ing and Director of Brown University’s Cen-ter for Biomedical Engineering.

Edith Mathiowitz, PhD, is Professorof Medical Science and Engineering andDirector of ABC Graduate Program atBrown Medical School.

Michael G. Ehrlich, MD, is VincentZecchino Professor and Chairman of Or-thopaedic Surgery at Brown MedicalSchool.

ACKNOWLEDGEMENTSFunding for this research comes

from a Veterans Affairs Rehabilitation Re-search and Development Center for Ex-cellence grant establishing the Center forRestorative and Regenerative Medicine,which is affiliated with the Providence VAMedical Center, Brown University andMIT.

Portions of this report have appearedin an abbreviated form in the JAAOS, Vol14, No. 10, pp. S198+.

CORRESPONDENCERoy K. Aaron, MDProfessor of Orthopaedic SurgeryBrown Medical School100 Butler DriveProvidence, RI 02906Phone: (401) 444-4485Fax: (401) 444-5006e-mail: [email protected]

Figure 5: Limb-lengthening

Fig. 5: The gap of lengthened bone with reconstitution of the periosteum andearly calcification.


Biomimetic Prostheses: The Next GenerationHugh Herr, PhD, and Samuel Au, MS�

PERHAPS THE MOST TANGIBLE COMPONENTSof biohybrid limb research are advancesin lower extremity prosthetic systems.These systems will employ biomimetic con-trol, muscle-like actuation, and neuro-sen-sors that will let leg amputees experienceimproved responsiveness to their actionsand wishes. The goal of this research is torestore amputee limb function to nearnormal levels. Specifically, we are achiev-ing improvement in gait stability andspeed, and metabolic economy of gait.

This research focuses on two lowerextremity systems: a variable-damper kneeprosthesis, and a motorized ankle pros-thesis. Unlike most current, passive pros-theses, these systems will simulate the dy-namics of joint impedance*. In addition,the system will contain mechanical powergeneration to better simulate the naturaldynamics of walking.

BACKGROUNDIn the 1970s, Professor Woodie

Flowers at MIT conducted research todevelop the prosthetic knee joint from apassive, non-adaptive mechanism to anactive device with variable damping ca-pabilities.1-4 Using the Flowers’ knee, theamputee experienced a wide range ofknee damping values throughout a singlewalking step. During ground contact,high knee damping inhibited knee buck-ling, and variable damping throughoutthe swing phase allowed the prosthesis toswing freely before smoothly decelerat-ing just prior to heel strike. While theFlowers’ knee was never sold commer-cially, several prosthetic companiesmanufactured similar variable-damperknee products.5 Actively controlled kneedampers offer advantages over mechani-cally passive knee systems. Most notably,amputees can change gait speed and de-scend inclines/stairs with greater ease andstability.6-8 Typically, ankle-foot systemscomprise elastomer* bumper springs orcarbon composite leaf springs (Figure 2)that store and release energy throughouteach walking or running step.5 Lowerlimb prosthetics, however, still do not re-store enough limb function. In order tomimic the behavior of the human ankle

and to increase gait symmetry and walk-ing economy, a prosthetic ankle-foot de-vice should actively control joint imped-ance, motive power, and joint position.

PROBLEMS ASSOCIATED WITHLOWER-EXTREMITY PROSTHESES

Commercially available lower-ex-tremity prosthetic devices do not varyspring stiffness or motive force like natu-ral limbs. Nor do they mimic the limbs’natural energy storage and return sys-tems. This causes many problems for legamputees. Recent studiessuggest that amputee bal-ance, especially when walk-ing over rough surfaces, mayimprove if the stiffness of theprosthetic ankle is adjustedin response to changes inground stiffness. In addi-tion, amputees using a pow-ered knee prosthesis canwalk at a faster pace andwith an improved metaboliceconomy compared to thosewith conventional knees,which only dissipate me-chanical energy.

The local mechanicalsensors employed in today’svariable-damper knee pros-theses are another limitationfor the leg amputee. With-out direct input from theuser to indicate intention,available prostheses cannotdetermine whether a patientwishes to turn to the right orto the left, or whether an ob-stacle falls directly in theamputee’s intended path-way. Since passive prosthet-ics place high metabolic de-mands on the body’sambulation systems, ampu-tees also typically experienceundue fatigue.9-11 In short,although some improve-ments have been observedwith variable-damper kneedesigns, problems still re-main.11

BIOMIMETIC ANKLE-FOOTPROSTHESIS DESIGN

Since the goal is to produce a pros-thetic that approximates a normal gait,research into the function of the humanankle during level-ground walking wasnecessary to provide the design specifi-cations for the ankle-foot prosthetic sys-tem.

The gait cycle begins with the heelstrike of one foot and ending at the nextheel strike of the same foot. The main sub-divisions of the gait cycle are the stance

Figure 1: Biomechanics of Level-groundWalking

The biomechanics of a normal human ankle duringlevel-ground walking can be broken into two phases,both of which consist of subphases. The swing phaserepresents the portion of the gait cycle when the foot isoff the ground. The stance phase begins at heel-strikewhen the heel touches the floor and ends at toe-offwhen the same foot rises from the ground surface.

There are four main mechanical elements in thehuman ankle-foot prosthesis: (a) a high power outputmotor (Maxxon RE-max 40), (b) transmission(gearhead and the bevel gears), (c) series springs, and(d) a carbon composite leaf spring prosthetic foot. Wecombine the first three components into a rotarySeries Elastic Actuator (SEA) to mimic the behaviorof the human ankle joint, while the elastic leaf springmimics the function of a human foot.

Figure 2: Mechanical Design of the HumanAnkle-foot Prosthesis


phase and the swing phase. The stancephase begins at heel-strike when the heeltouches the floor, and ends at toe-off,when the same foot rises from the groundsurface. Stance phase can be subdividedinto three sub-phases: controlled plantarflexion, controlled dorsiflexion, and pow-ered plantar flexion. The swing phaserepresents the portion of the gait cyclewhen the foot is off the ground.

Research into gait mechanics allowedresearchers to design an ankle-foot pros-thesis that mimics the biomechanics of anormal limb during walking. We devel-oped a finite state machine* to implementthe basic control system for the prosthe-sis. As in normal walking, the prosthesiswas controlled as a linear torsional springwith stiffness KCP in controlled plantarflexion. (Figure 1) In controlled dorsi-flexion, we simply used two linear springsto approximate the nonlinear spring be-havior of the human ankle. In the design

process, several criteria for biomimeticfunction were established. Much like anatural ankle, the biomimetic ankle wasmodeled as a torque source in series withthe controlled dorsiflexion spring, andadditional amounts of energy can beadded to the ankle joint during poweredplantar flexion. In addition, the pros-thetic ankle must be capable of chang-ing its stiffness within each phase of gait;and it must be capable of controlling jointposition during the swing phase.

There are four main mechanical el-ements in the system we designed to pro-vide these capacities: (a) a high power out-put motor, (b) transmission (gear headand the bevel gears), (c) series springs, and(d) a carbon composite leaf spring pros-thetic foot. The first three componentsare termed a rotary Series Elastic Actua-tor (SEA) and mimic the behavior of thehuman ankle joint, while the elastic leafspring mimics the function of a humanfoot. (Figure 2)

A Series Elastic Actuator has beenpreviously developed for legged robots.It consists of a dc motor in series with aspring (or spring structure) via a me-chanical transmission. The SEA provides

precise force control by controlling theextent to which the series spring is com-pressed. An SEA has several biomechani-cal features that make it a good choicefor human rehabilitation applications.SEAs are force controllable actuators;they are safer to use with human subjectsthan direct drive systems because a limit-ing maximum force can be specified thatwill not cause harm to the human user.A prototype of the actual prosthesis isshown in Figure 3. The specifications ofthe prosthetic system are listed in Table1.

Because we believe that theamputee’s device acceptance and comfortshould be criteria for selecting certainadjustable values—such as spring stiffnessand the amount of power generated dur-ing specific phases of the walking gait—in our initial pilot investigations, we feltit was reasonable to allow the subject toselect these parameters based on his/herown walking preferences. To achieve thisgoal, we developed a graphical user-in-terface that allows the amputee to adjustthe settings and timing of these values.

In our pilot study, the subject se-lected a stiffness value that eventually con-verged to the normalized biological valuewe had established during our study ofthe biomechanics of the walking gait. Par-ticipant comments confirmed that thevirtual spring improved shock absorptionduring heel-strike and also allowed for asmoother transition from ControlledPlantar Flexion to Controlled Dorsiflex-ion. During its use, we observed that theprosthesis behaved more naturally thana conventional passive prosthesis and al-lows for a more natural gait.

REFERENCES1. Flowers WC. A Man-Interactive Simulator System for

Above-Knee Prosthetics Studies. PhD thesis, MIT, De-partment of Mechanical Engineering, 1972.

2. Donath M. Proportional EMG Control for Above-KneeProsthesis. MS and ME thesis, MIT, Department of

Table 1: A summary of thespecifications for the ankle-foot design.

Current A 75kgDesign person

Peak Power 440W 240W

Peak Torque 340 Nm 127.5Nm

Peak Velocity 25 Nm 19 Nmat 5 at 5rad/sec rad/sec

Weight 2.5kg N/A

Height 0.32m N/A

Max. Allowable

Dorsiflexion 25 deg 25 degMax. Allowable

Plantar Flexion 45 deg 45 deg

Commerciallyavailable lower-

extremity prostheticdevices do not varyspring stiffness ormotive force like

natural limbs.

A photograph of the biomimetic ankle-foot prosthesis prototype (left) anda SolidWorks model next to a human foot (right).

Figure 3: Prototype ankle-foot prosthesis GLOSSARYJoint impedance: The stiffness and

damping of a jointElastomer: Any of various elastic

substances resembling rubberFinite State Machine: A programming

structure comprising distinct statesand transitional conditions be-tween states


Neuromotor Prosthesis DevelopmentJohn P. Donoghue, PhD, Leigh R. Hochberg, MD, PhD, Arto V. Nurmikko, PhD, Michael J. Black, PhD,

John D. Simeral, PhD, and Gerhard Friehs, MD

UNLIKE HUMAN LIMBS, TRADITIONAL, PAS-SIVE PROSTHESES have practically no abil-ity to respond to anything but the mostbasic aspects of our movement intentions.In addition, traditional prostheses cannotcommunicate sensory information to thebrain. Biohybrid limb research seeks torestore sensory and motor signals meantfor natural limb function by creating aninterface that provides two-way commu-nication between the prosthetic limb andthe nervous system. The goal of our re-search is to create a biohybrid interfacethat communicates directly with the ner-vous system.

NEUROMOTOR PROSTHESES (NMPS)In the human nervous system, sen-

sory and motor information are repre-sented in patterns of electrical impulses(neuronal action potentials), often calledspikes. Research into these patterns haspaved the way for the development ofclosed-loop neuromotor prostheses(NMPs), which have the potential to en-able bidirectional interaction between thehuman nervous system and external de-vices. In the case of semiautonomousrobots, such devices could be indepen-dent of the human body, but capable ofcommunicating with and being con-trolled by human users. In the case of

�

Figure 1. Basic elements of brainmachine interface

This bidirectional system must have an interface todetect neural signals (Sensor), a decoder to trans-form the neural signal into a desired command sig-nal, and a controlled device, such as a computer, ro-bot, or muscle. For a closed-loop system, feedbackreports error in uncertain environments.

Mechanical Engineering, 1974.3. Tanquary ML A Microprocessor Based Prosthesis Con-

troller for Use During Early Walking Training of Above-Knee Amputee. MS thesis. MIT, Department of Me-chanical Engineering, 1978.

4. Schechter SE. 1981. Passive Self-Contained Micro-computer Controlled Above-Knee Prosthesis. MS the-sis. MIT, Department of Mechanical Engineering,1981.

5. Dietl , Bargehr H. 1997. Der Einsatz von Elektronikbei Prothesen zur Versorgung der unteren Extremitat.Med Orth Tech 1997; 117: 31-5.

6. Kastner J, Nimmervoll R, et al.. A comparative gaitanalysis of the C-Leg, the 3R45 and the 3R80 pros-thetic knee joints, 1998. http://www.healthcare.ottobock.com.

7. Herr H, Wilkenfeld A. User-adaptive control of amagnetorheological prosthetic knee. Industrial Ro-bot: An Internat J 2003; 30: 42–55.

8. Gonzalez EG, Corcoran PJ, Rodolfo LR. Energyexpenditure in B/K amputees: correlation with stumplength. Arch Phys Med Rehabil 1974;55: 111-9.

9. Waters R, Perry J, et al. Energy cost of walking am-putees. J. Bone Jt Surg 1976; 58A: 42-6.

10. Esquenazi A, DiGiacomo R. Rehabilitation afteramputation. J Am Podiatr Med Assoc 2001;91:13-22.

11. Lellas J, Thakkar S, et al. Hydraulic versusmagnetorheological- based knee prostheses. Trans-actions on Neural Systems & Rehabilitation Engineer-ing (In press).

ACKNOWLEDGEMENTS:Funding for this research comes

from the Veterans Affairs RehabilitationResearch and Development Center forExcellence grant establishing the Centerfor Restorative and Regenerative Medi-cine, which is affiliated with the Provi-dence VA Medical Center, Brown Uni-versity, and MIT.

Portions of this report have appearedin an abbreviated form in the JAAOS, Vol14, No. 10, pp. S198+.

Hugh Herr, PhD, is Assistant Profes-sor in the Program in Media Arts and Sci-ences with the MIT-Harvard Division ofHealth Sciences and Technology, and Di-rector, Biomechatronics Group, MIT Me-dia Laboratory.

Samuel Au, MS, is a graduate studentin the Department of Mechanical Engi-neering, MIT. He is pursuing a PhD andconducts research within theBiomechatronics Group at MIT.

CORRESPONDENCEHugh Herr, PhDMIT Media Laboratory, Room E15-419Cambridge, MA 02139Phone (617) 253-6780e-mail: [email protected]

biohybrid limb prostheses, the devicesthemselves could replace limbs lost sec-ondary to traumatic amputation, vascu-lar or medical disease, and the ideal pros-thesis would mimic both natural motionand sensation.

The emerging technology of NMPscombines cutting-edge biomedicine,neuroscience, mathematics, computerscience, and engineering. This type of in-terface transcends earlier controllers be-cause it is based on neural spiking, asource of information-rich, rapid, com-plex control signals from the nervous sys-tem. NMPs promise an entirely newparadigm for building bionic systems thatcan restore lost neurological functions.

For example, our team, together witha Brown spin-off company,C y b e r k i n e t i c sNeurotechnology Systems, Inc.(CKI), has already created asystem that records humanbrain signals, decodes them,and transforms them intomovement commands. Thesystem consists of a match headsized platform with 100thread-thin electrodes thatpenetrate just into the surfaceof the motor cortex wherecommands to move the hand

emanate. The pattern of complex neuralsignals is decoded by a rack of computersthat displays the resultant output as themotion of a cursor on a computer moni-tor—as if the thoughts to move the handhad moved a computer mouse. This neu-ral command signal has been used by per-sons with tetraplegia to control a computerfor spelling1, to run software, or to useassistive devices that control a television.2

While computer cursor motion representsa form of virtual device control, this samecommand signal could be routed to anyof a number of devices to command mo-tion of paralyzed muscles or the actions ofprosthetic limbs; indeed, simple roboticarm control has already been achieved inpilot studies2 and we have achieved pre-


liminary control of an electric wheelchair.1

Joining expertise in human functionalneurosurgery and neurology (Friehs andHochberg), computer science and robot-ics (Black), neuroscience (Donoghue), andengineering (Nurmikko), this team has al-ready completed initial work on potentiallycommercial elements of first-generationNMP technology now being developedthrough CKI.

To make further progress towards auseful product, the current pilot systemmust become miniaturized, wireless andfully implantable. Our team is develop-ing these key elements of advanced NMPtechnology: integrated microscale signalprocessors, innovative broadband opticaltelemetry and powering, and miniaturizedprocessors are all in development. Reli-able signal control is also essential for day-to-day use. We are working on new math-ematical models to transform a smallsample of human neural recordings into arich and useful control signal. In addi-tion, we are working to create an inter-face that can provide sensation via low lev-els of patterned electrical stimulation to thesensory areas of the brain. In this way wehope to provide an NMP that creates two-way communication between machinesand the nervous system.

RESEARCH AND TRANSLATIONALGOALS

This research provides the founda-tion for a system that could ultimatelyallow paralyzed people a greater degree

of independence, communication andmobility if they were able to control –simply through their own movement in-tentions – computer, robotic, or pros-thetic interfaces. Long-term goals in-clude a new class of devices necessary forhuman NMPs to operate more effec-tively, and to elucidate the principles oftheir operation. Intermediate goals in-clude the development of both controlalgorithms and user interfaces thatwould enable human neural control ofrobot navigation tasks or other complexinteractions.

Modeling the Brain ComputerInterface

The initial technology of Brain Com-puter Interfaces (Figure 1), of whichNMPs are one type, consists of three keycomponents: a neural interface, a decod-ing system, and a user interface (effec-tor); a closed-loop system would be com-pleted by a feedback signal from the ef-fector to the brain. Feedback would beachieved by very low level electrical im-pulse sequences that attempt to activatea neural apparatus that participates in sen-sation. Core elements of the current re-search include:

1. An optimally designed and exten-sively tested microelectrode array.Microelectrode array fabrication in-corporates controlled design andmanufacturing of a one-hundredelectrode sensor, a compact 4 x 4

mm device that com-municates with exter-nal electronics via an~ 13 cm cable and apercutaneous Ti ped-estal. Long-term pre-clinical studies in Dr.Donoghue’s labora-tory showed that thearray is sufficientlystable to providelong-term recordingof neuronal spikessuitable for NMPuse.3 The implanttesting and designwas submitted to theFDA for a proposedpilot clinical trial in2004.

Microsystem with an active im-plantable unit in soft encapsula-tion; transdermal IR telemetry; in-ductively or IR coupled powereddelivery clock

Implantable microsystem con-nected to subcutaneous highspeed fiber optic link; IR powerdelivery and telemetry throughsubcutaneous fiber coupled toobdominal/chest cavity unit.

This illustrates two adaptations of the same basic microsystemdesign for high-fidelity transcutaneous neural signal extractionat high data rates.

Figure 2. Implatable cortical micosystem overview

2. Signal acquisition and processing byspecialized microelectronic devicetechnology. A complete system isproduced by Cyberkinetics, andminiaturized versions are being de-veloped by our group to make thedevices fully implantable, auto-mated and portable.

3. Decoding based upon a principledmathematical framework has beendeveloped by Drs. Black andDonoghue and their colleagues. De-coding efforts attempt to extract themaximum amount of information re-lated to movement intentions fromthe sample of neurons detected us-ing the implant. The signal is usedfor real-time control. Computationalmethods for signal processing are usedto improve the quality of control.These methods attempt to achieve thespeed and accuracy of an able-bod-ied human using a computer mouseto operate a standard PC.

4. Implementation of decoded signals asa control source. Once a brain de-rived control signal has been created,it can be used to operate a wide rangeof devices that improve indepen-dence, mobility and communicationfor those with limited movement abili-ties. Control signals can be used torun a computer and assistive technolo-gies. In addition, control signals havebeen used to direct robotic arms. Thesignals are also potentially useful to re-animate limbs by driving electricalstimulators in paralyzed but otherwiseoperational muscles or actuators inadvanced prosthetic limbs.

DECODING THE HUMAN BRAINDecoding is the task of transform-

ing complex neural patterns into a mean-ingful control signal that can drive physi-cal or biological devices. This involves twokey parts: First, we must understand howthe brain adapts to control new devicesand how we can best train the brain tocontrol a new motor system. Second, wemust mathematically model the way neu-ral signals encode information aboutmovement, and then exploit these mod-els to develop a real-time “translator” be-tween the neural signals and the inputsneeded to control new devices.


We have made substantial progressin this task. Using mathematical algo-rithms, we can convert motor cortex spik-ing activity into a continuous reconstruc-tion of hand position, and classify pat-terns of motor cortex activity into discretechoices.4-7 Recently we have developed“multi-state” methods that enable thedecoding of continuous cursor trajecto-ries and discrete “click” activities from thesame population of cells.8 Unique to thisendeavor is the need to develop trainingmethods parallel to new decoding algo-rithms; in designing algorithms one musttake into account how the brain learnsand how best to train it.

Accurate decoding can create aricher repertoire than current, fairlysimple, scenarios in which the decodingof hand motion is either in one of a fixednumber of directions or is a continuousreconstruction of two-dimensional handtrajectory. Our principled mathemati-cal approach provides the foundation toenable the control of physical devices suchas wheelchairs, prosthetic arms and dex-terous robot hands. In particular, taskssuch as manipulating, grasping, pushing,and gesturing involve the composition ofmore primitive motions. For example,even a simple action such as picking up ablock may be composed of a preparationphase, a ballistic hand transport motion,manipulator positioning using visualservoing, and, finally, a grasping motion.Ultimately, the challenge is to develop aprosthetic device under neural controlthat is capable of executing all such com-positional actions. Achieving this high-di-mensional control will require basic sci-entific and engineering advances to de-termine the full extent of informationavailable from neural spike trains.

Challenges remain, however. Forexample, decoders in use day to day bypatients will need to function adaptivelyto deal with changes in the system thatcan arise from instabilities in the sensorsor in the biological system. In addition,available neurons may change over timeas sensors move even slightly in the tis-sue. For development purposes, wesimulate more complex actions on a com-puter screen, where we can readily con-trol the properties of a wide range ofdevices. This knowledge will set the stagefor the development of actual devicesthat can serve real world interactions,

such as navigation in complex environ-ments or control of multidimensionalmanipulators requiring dexterous fin-ger, hand, and arm movements of an ar-tificial device.

RESEARCH TOWARDS WIRELESSFULLY IMPLANTABLE NEURALINTERFACES

The overall goal of this project is todevelop a fully implantable wireless multi-neuron sensor for broad research, neuralprosthetic, and human neurodiagnosticapplications. The implantable microsystemis based on the sensor electrode platformwhich has been extensively evaluated inpreclinical animal studies, and now in fourtetraplegic humans who are part ofCyberkinetics’ BrainGate pilot clinical tri-als. Related work aims to achieve multi-sitestimulation to serve as an input interfacefor human and animal research applica-tions.

The miniaturized brain implantableNMP microsystem-on-chip now underdevelopment at Brown has unique designfeatures; it is flexible and scalable to al-low transmission of increasingly largeramounts of neural information from thecortex to assistive technologies. Themicrosystem design architecture is alsocompatible with the longer term pros-pects of connecting the motor cortex tomuscle nerves intra-corpus via a fiber op-tical network within the body, as well asvia external prosthetic devices. In thedevelopment of the new NMP technol-ogy, we will be guided by experiencegained from ongoing BrainGate humantrials that employ passive microelectroderecording arrays, which are coupled by apercutaneuous connector to external elec-tronic modules.

Early prototypes of the implantablemicrosystems are under way, which in-corporate advanced ultra-low power mi-croelectronic circuits and processorswith optoelectronic devices as integratedcortical implants, shown schematically inbroad overview in Figure 2. This projectcharts a new pathway to humanneuroprosthetics, well beyond the cur-rent state-of-the-art, while ultimately en-deavoring to create a platform for a newneuro-technology paradigm for “whole-body” prosthetic networking via corti-cal interfaces. The design of the new im-plantable NMP microsystems will lever-

age information acquired from humanclinical trials, including the experiencegained with the present external cablingsystem developed by Cyberkinetics. Thegoal of the microsystem-on-chip is to en-able very high data rate wireless trans-mission of high fidelity neural signals(spikes and LFPs) with transcutaneouspowering and signal transmission. Wehave already achieved an initial proto-type 16-channel microsystem which hasbeen tested at the benchtop and initialrat animal studies.

CONCLUSIONSAs they apply to biohybrid limb re-

search, on-going advances in neural in-terfaces, microelectronic devices and de-coding may allow dynamic linkages be-tween the cortex and robotic prosthesesthrough novel systems, such as the NMPsystem we are developing. Ultimately,these technologies could provide directbrain control of artificial limbs for am-putees, or direct control of muscles forthose with paralysis, as well as an entirelynew means for physical monitoring andrepair of the human nervous system.

John P. Donoghue, PhD, is HenryMerritt Wriston Professor and Director ofthe Brain Science Program at Brown Uni-versity, and Co-founder and a Director ofCyberkinetics, makers of the BrainGateTechnology.

Leigh R. Hochberg, MD, PhD, is As-sociate Investigator, Rehabilitation Re-search and Development Service, Provi-dence VA Medical Center, Investigator ofNeuroscience in the Division of Biology andMedicine at Brown Medical School andInstructor in Neurology, Harvard Medi-cal School.

Arto V. Nurmikko, MD, PHD, is theL. Herbert Ballou Professor of Engineeringand Physics Electrical Sciences and Com-puter Engineering at Brown University.

Michael J. Black, PhD, is Professor ofComputer Science at Brown University.

John D. Simeral, MSEE, PhD Neu-roscience, is a Postdoctoral Fellow, Rehabili-tation Research and Development Service,Dept of Veterans Affairs Medical Center,Providence, RI.

Gerhard Friehs, MD, is Associate Pro-fessor of Clinical Neuroscience at BrownUniversity.


ACKNOWLEDGEMENTSAll of the authors, or the departments

with which they are affiliated, have receivedresearch or institutional support from theCenter for Restorative and RegenerativeMedicine, which is affiliated with the Provi-dence VA Medical Center, Brown Univer-sity, and MIT. The Center is funded by aVeterans Affairs Rehabilitation Researchand Development Center for Excellencegrant. Dr. Hochberg has received researchor institutional support from CyberkineticsNeurotechnology Systems, Inc. Dr.Donoghue has stock or stock options heldin Cyberkinetics Neurotechnology Systems,Inc. Dr. Friehs serves as a consultant toCyberkinetics Neurotechnology Systems,Inc. The authors thank Margaret Case forher assistance in reviewing this article.

Portions of this research have ap-peared in an earlier and abbreviated formin the JAAOS, Vol 14, No. 10, pp. S198+.

REFERENCES1. Donoghue JP,. Friehs GM, et al.. BrainGate

neuromotor prosthesis. Society for NeuroscienceAbstracts 2006; 256.10.

2. Hochberg LR, Serruya MD, et al. Nature2006;442:164-71.

3. Suner S, Fellows MR, et al. Reliability of signalsfrom a chronically implanted, silicon-based elec-trode array in non-human primate primary mo-tor cortex. IEEE Trans Neural Syst Rehabil Eng2005;13:524-41.

4. Maynard EM, Hatsopoulos NG, et al. Neuronalinteractions improve cortical population coding ofmovement direction. J Neurosci 1999;19:8083-93.

5. Serruya M Hatsopoulos N, et al. Robustness ofneuroprosthetic decoding algorithms Biol.Cybern.; DOI 10.1007/s00422-002-0374-6Online publication: February 21, 2003

6. Wu W, Black MJ, et al. Neural decoding of cur-sor motion using a Kalman filter, in: Adv NeuralInf Process Syst 15, MIT Press, 2003

7. Gao Y, Black MJ., et al. Probabilistic inference ofhand motion from neural activity in motor cor-tex. Adv Neural Inf Process Syst 14, The MITPress, 2002.

8. Wood F, Prabhat, et al. Inferring attentional stateand kinematics from motor cortical firing rates,Proc. IEEE Engineering in Medicine and Biol-ogy Society, pp 1544-7, Sept. 2005.

CORRESPONDENCEJohn P. Donoghue, PhDProfessor of NeuroscienceBrain Science Program, Box 1953Brown UniversityProvidence, RI 02912Phone: (401) 401-863-2701e-mail: [email protected]

Identifying Clinically Meaningful Improvement InRehabilitation of Lower-Limb Amputees

Linda Resnik, PhD, PT, OCS�THE EFFECTIVENESS OF TISSUE ENGINEERING,and both surgical and prosthetic inter-ventions for lower limb amputees mustbe assessed rigorously through carefullydesigned outcome studies. While objec-tive measurements such as faster gaitspeed and better balance are importantways of evaluating rehabilitation success,they are insufficient without an assess-ment of the patient’s subjective experi-ence of intervention effectiveness. Thus,the outcomes that we use to evaluate ourinterventions will include physical per-formance measures as well as measuresof the amputee’s subjective experience ofprosthetic satisfaction, quality of life, andmobility.

For small groups of subjects, thechoice of highly reliable and responsiveoutcomes measures is imperative. Thebest instruments for use with individualpatients and small group studies havesuperior measurement properties: in par-ticular, reliability, measurement range,and responsiveness. However, not allmeasurements work with individuals orsmall groups. Scales with large floor orceiling effects, or substantial numbers ofpatients scoring at the bottom or top ofthe scale, for example, are not appropri-ate choices for measuring individual-level

change. In addition, some instrumentsmay lack the psychometric properties thatdetect change on the individual level.1 Toassess the effectiveness of interventions inclinical practice and small studies, mea-sures must be responsive to change on anindividual level, and research on respon-siveness must assist in interpretation ofscores.

In large clinical trials, the effective-ness of interventions is assessed statistically,by comparing mean change in outcomesscores between groups of patients. Thesesame comparisons are impossible in clini-cal practice or trials using very smallsamples. Thus, common measures of re-sponsiveness—such as effect size,2 stan-

dardized response means,3 or the respon-siveness statistic4—summarize test respon-siveness and are useful for making rela-tive comparisons between measures, butdo not contribute to the interpretationof test results in individual subjects or pa-tients.5 For interpretability at the indi-vidual level, one should be able to answerquestions such as, “Does a change in scoreof 10 points in a certain measure denotean important change for these patients?”and “Is a 5-point change in score thesame as a 10-point change in score?”

Data on two properties, minimumdetectable change (MDC)6-8 and mini-mal clinically important difference(MCID)9.10 can assist in interpretingscores for individuals and small groupsof patients. Minimum detectable changeis a statistical measure of meaningfulchange, defined as the minimumamount of change that exceeds measure-ment error.8 From a statistical perspec-tive, an individual patient is consideredto have changed only when the differ-ence between the previous score and thecurrent score exceeds the MDC associ-ated with the measurement.7 MCIDs, onthe other hand, define the threshold atwhich an individual has experienced aclinically relevant change.9,10

In the ceiling effect,there is little room

for patients to showimprovement,because they

already score at thehigh end of the

scale.


Table 1: Physical Performance and Self-Report Assessment MeasuresUndergoing Analysis

PHYSICAL PERFORMANCE MEASURESTimed walk testsTwo and six minute timed walking tests are designed to assess mobility, and orcardiovascular fitness. The distance covered in the allotted time is taken as themeasurement of performance.

Timed Up and GO (TUG)The TUG is a brief performance based measure of basic mobility that incorpo-rates walking and turning while walking, balance and transfers.

Amputee Mobility Predictor (AMP)The amputee mobility predictor is an instrument designed to measure ambula-tory potential of lower-limb amputees both. The AMP consists of twenty oneitems that evaluate ability in transfers, sitting and standing balance as well asgait skills.

SELF-REPORT MEASURESSF-36SF-36 is a generic instrument containing 8 different scales measuring physicaland mental health constructs. Three of the SF-36 scales will be tested, GeneralHealth, Physical Function, and Role Physical.

PEQThe Prosthetic Evaluation Questionnaire (PEQ), is a condition specific instru-ment developed for prosthetic users. We will test four of the PEQ’s nine scales:General Health, Mobility, Transfers and Prosthetic Utility

OPUSThe Orthotics and Prosthetics Users Survey (OPUS) is a condition specificinstrument that measures outcomes pertinent to prosthetic as well as orthoticusers.6 Three of the OPUS’s four scales will be tested Lower limb functionalmeasure, Health Related Quality of Life scale, and the Follow-up Evaluation ofSatisfaction with Device scale.

Patient Specific Functional Scale (PSFS)In the PSFS, the patient is asked to select up to five main activities that he orshe finds difficult to do because of the amputation. Then the patient is asked toprovide a rating of his or her current ability to complete these activities.

The goal of my current research is tocreate more appropriate and productiveoutcome measures for lower limb ampu-tees using recent advances in the selectionand interpretation of assessment measures,specifically in the areas of responsiveness,sensitivity to change, and the interpretabil-ity of measurement change scores. Becausethis study is designed to integrate patientself-reports with performance-based mea-sures of limb function, this study covers arange of both types of assessment measures.This will be a multi-site study with re-peated measurements of subjects. Datawill be collected at five sites (the Provi-dence, Boston, and Miami VA MedicalCenters, and two other non-VA hospitals).The tests are being administered by physi-cal therapists observing and grading physi-cal performance of activities.

measures. Our first method, modeledafter that used by Jaeschke9 and Juni-per12, will calculate the mean change insubscale score that corresponds tochanges in external criteria. Our secondmethod, modeled after Stratford,11

Riddle,13 and Bruynesteyn,14 will em-ploy diagnostic test methodology anduse information from stable andchanged patients. In this method, theMCID of each self-report instrumentsubscale will be compared by develop-ing receiver operating characteristic(ROC) curves.

In both methods, external criteria(anchors) will be used to identify patientswho have changed by a clinically mean-ingful amount. We expect that the use ofthese two methods and variety of exter-nal criteria will yield variability in MCIDcalculations, allowing us to obtain a rangeof MCID parameters that can be usefulfor interpretability of score change.

At the end of our analyses we willhave accumulated data on MDC as wellas MCID calculated by ROC and meanscore change method. We will aggregatethe evidence from these analyses to makerecommendations on the proper inter-pretation of change scores for each mea-sure. Several authors have highlightedthe merits of triangulating both distribu-tion and anchor based approaches todefine meaningful changes.15-18 Using tri-angulation, we will also be able to makerecommendations about those self-reportinstruments that are the most sensitiveand responsive to change.

CORRECTING FOR FLOOR ANDCEILING EFFECTS

Another problem in current out-come instruments is the inability to mea-sure change for patients who fall outsideranges of test expectation. These “floorand ceiling” effects occur when an instru-ment lacks sufficient scale range, result-ing in a large proportion of scores at thevery top or bottom of the range. In theceiling effect, there is little room for pa-tients to show improvement, because theyalready score at the high end of the scale.For example, an amputee patient who isable to run, but is limited to short dis-tances, might score off the charts, despiteself-reported frustration with the unduefatigue caused by higher rates of meta-bolic stress related to prosthetic use.

MEASURING DETECTABLE CHANGEIn order to be responsive to change,

measurement instruments must detectchange when it has occurred, and re-main stable when change has not oc-curred. The ability of an instrument todetect relevant clinical change as judgedby an external criterion, a type of con-struct validity, is considered by some tobe the most important measurementproperty for evaluating a scale’s useful-ness in making individual patient deci-sions.11

Prior research suggests that theremay not be a single MCID value that isapplicable across all patients because theMCID of instruments can vary depend-ing on the patient’s baseline state andthe methodology used to calculate it.7

Thus, we are using several methods tocalculate the MCID within self-report


One aim of this study is to identifyscales with large floor or ceiling effects,which are inappropriate choices for mea-suring individual-level change. We willassess the extent of floor and ceiling effectsusing two methods. First, we will examinethe distribution of scores for each scale,observing the shape and presence of scoreclustering. Scores clustered at the low endof the scale suggest the presence of flooreffect, whereas scores clustered at the highend of the scale would suggest presenceof a ceiling effect. Next, we will calculatethe minimum and maximum scale scoresaround which the MDC could be placedwhile maintaining the score above thebottom (floor) and below the top (ceil-ing) and then calculate the percentage ofthe sample achieving scores that rangewithin the MDC of the lowest (floor ef-fect) and highest (ceiling effect) for eachsubscale. Scales with large floor or ceilingeffects would not be appropriate choicesfor measuring individual-level change andwill not be included in our future testing.

STUDY MEASURESTwo types of measurement instru-

ments will be tested in this study: self-re-port measures of health-related quality oflife (HRQL) and performance-basedmeasures of mobility. Self-report HRQLinstruments use patient questionnaire re-sponses to measure multiple domains ofhealth that include physical, psychologi-cal, emotional, and social dimensions.19

The self-report instruments include theProsthetic Evaluation Questionnaire(PEQ),20 the SF-36,21 the Orthotics andProsthetics Users’ Survey (OPUS),22 andthe Patient-Specific Functional Scale(PSFS).23 The performance measureschosen for this study are the two- and six-minute walk tests,24 the Timed Up andGo (TUG) and the Amputee MobilityPredictor.25 Each instrument is describedbelow. (Table 1)

We will use global transition ratingsas an external criteria for change in self-report measures. Three separate transi-tional scales will be used, one for generalhealth, one for prosthetic satisfaction, andone for physical function. We will clas-sify subjects as having either changed orremained stable by asking if there has beenany change in their overall health, pros-thetic satisfaction and physical functionin the last 4 weeks. Next, using the 3 sepa-rate global change scales, subjects will ratethe amount of change they have experi-enced on a scale of -7 (much worse) to+7 (much better). Use of global changeratings has face validity, as retrospectiveappraisal by the patient is widely used inclinical practice to assess change and hasbeen found to be highly correlated withtreatment satisfaction.26

This work is designed to provide pa-rameters for the continued evaluation ofprosthetic and rehabilitation interven-tions that will help physicians, cliniciansand patients establish shared values foroutcomes measurements that are statisti-cally valid and that can be tracked overtime. Ultimately, the goal is method-ologically sound clinical trials and assess-ment instruments that will improve pa-tient care even as they allow researchers,prosthetists and physical therapists tomonitor, track and assess informationabout limb function, overall mobility, andprosthetic satisfaction.

ACKNOWLEDGEMENTSThe author would like to acknowl-

edge Vince Mor, PhD, Chairman of theDepartment of Community Health,Brown University, for his assistance in thisresearch endeavor.

Funding for this research comesfrom the Veterans Affairs RehabilitationResearch and Development Center forExcellence grant establishing the Centerfor Restorative and Regenerative Medi-cine, which is affiliated with the Provi-dence VA Medical Center, Brown Uni-versity, and MIT.

REFERENCES1. Riddle DL, Lee KT, Stratford PW. Med Care

2001;39:867-78.2. Kazis LE, Anderson JJ, Meenan RF. Med Care

1989;27 (Suppl):S178-89.3. Cohen J. Statistical power analysis for the behav-

ioral sciences. 2nd ed. Hillsdale, N.J.: L. ErlbaumAssociates; 1988.

4. Guyatt G, Walter S, Norman G. J Chronic Dis1987;40:171-8.

5. Kennedy DM, Stratford PW, et al. BMCMusculoskelet Disord 2005;6:3.

6. Fritz JM, Irrgang JJ. Et al. Control Clin Trials1989;10:407-415e. Physical Therapy2001;81:776-88.

7. Stratford PW, Binkley J, et al. Phys Ther.1996;76:359-65; discussion 366-58.

8. Wyrwich KW, Tierney WM, Wolinsky FD. J ClinEpidemiol 1999;52:861-73.

9. Jaeschke R, Singer J, Guyatt GH. Control ClinTrials 1989;10:407-15.

10. Beaton DE, Bombardier C, et al. J Clin Epidemiol.2001;54:1204-17.

11. Stratford PW, Binkley JM, et al. Phys Ther.1998;78:1186-96.

12. Juniper EF, Guyatt GH, et al. J Clin Epidemiol.1994;47:81-7.

13. Riddle DL, Stratford PW, Binkley JM. PhysicalTherapy 1998;78:1197-207.

14. Bruynesteyn K, van der Heijde D, et al. JRheumatol 2001;28:904-10.

15. Haley SM, Fragala-Pinkham MA. Phys Ther2006;86:735-43.

16. Eton DT, Cella D, et al. J Clin Epidemiol2004;57:898-910.

17. Cella D, Bullinger M, et al. Mayo Clin Proc.2002;77:384-92.

18. Yost KJ, Cella D, et al. J Clin Epidemiol.2005;58(:1241-5.

19. Jette AM. Physical Therapy 1993;73:528-37.20. Legro MW, Reiber GD, et al. Arch Phys Med

Rehabi. 1998;79:931-8.21. Ware J Jr. Snow KK, et al. SF-36 Health Survey:

Manual and Interpretation Guide. Boston: The HealthInstitute, New England Medical Center; 1993.

22. Heinemann AW, Bode RK, O’Reilly C. ProsthetOrthot Int. 2003;27:191-206.

23. Stratford P, Gill C, et al. Physiotherapy Canada.1995;47:258-63.

24. Butland RJ, Pang J, et al. Br Med J (Clin Res Ed).1982;284:1607-8.

25. Gailey RS, Roach KE, et al. Arch Phys Med Rehab2002;83:613-27.

26. Fischer D, Stewart AL, et al. JAMA1999;282:1157-62.

Linda Resnik, PhD, PT, OCS, is a re-search Health Scientist at the ProvidenceVA Medical Center and Assistant Profes-sor of Community Health at Brown Medi-cal School.

CORRESPONDENCELinda Resnik, PhD, PT, OCSProvidence VA Medical Center830 Chalkstone AvenueProvidence, RI 02908Phone: (401) 863-9214e-mail: [email protected]





Blast Injuries In Civilian PracticeChristopher T. Born, MD, FAAOS, FACS, Ryan Calfee, MD, Joann Mead, MA�

ALTHOUGH EXPLOSIONS UNRELATED TOTERRORISM occasionally occur in indus-trial settings, within today’s geopoliticalenvironment explosions and bombingsare all too commonly the primary disas-ter “events” to which both civilian andmilitary medical/surgical personnel rou-tinely must respond. Indeed, data fromthe RAND®-MIPT Terrorism Incidentdatabase show that bomb blast injuriesworldwide account for 82% of all inju-ries caused by terrorists. (Figure 1)

As terrorists expand their operations,injuries from blast are unfortunately be-coming more common in the non-mili-tary population. Recent terrorist inci-dents such as Oklahoma City in 1995,2

Atlanta’s Centennial Olympic Park in1996,3 Manchester, England in 1996,4

the multiple bombings in Madrid, Spainin 2004,6 and the train and bus explo-sions in London on July 7, 2005,6 haveprovided investigators much opportunityto study blast injury in greater detail. Outof necessity, the military has expanded itsunderstanding and ability to manageblast-related injuries. However, the ci-vilian medical community remains rela-tively unprepared. In a membership sur-vey conducted by the Eastern Associa-tion for the Surgery of Trauma (EAST),only 73% of the trauma surgeon-respon-dents felt that they had an adequate un-derstanding of the pathophysiology andclassification of blast injuries.7

This knowledge is crucial. Knowl-edge of the blast scene and blast mechan-ics can improve triage at the disaster sceneand/or in the emergency room. In addi-tion, triage teams trained to respond toblast scenarios can determine how effi-ciently potentially scarce or overbur-dened local resources are utilized. Oneremarkable example was the response tothe simultaneous detonation of 10 explo-sions on commuter trains in Madrid,Spain on March 11, 2004: 177 peoplewere killed at the scene; over 2000 werewounded.9 Of this number, 966 civil-ians were transported to hospitals.Gregorio Maranon University GeneralHospital, which was closest to the disas-ter scene, received 312 patients, 91 of

whom were hospitalized. Resources em-ployed for this event reportedly includedmore than 70,000 health personnel, 291ambulances, 200 firemen, 13 psychologyunits, 500 volunteers, and thousands ofblood donors. Emergency communica-tion centers received over 20,000 callsthat morning. At Gregorio Maranonalone, 272 victims were treated between8:00am and 10:30am. In immediateresponse to the blast, all surgeries in 22operative suites were cancelled and 161patients were discharged in 2 hours.9

Triage errors are categorized asundertriage or overtriage. Undertriage isthe assignment of critically injured casu-alties needing immediate care to a de-layed category. This may lead to prevent-able deaths. It can be avoided by train-ing triage officers to recognize life-threat-ening problems requiring urgent treat-ment. Overtriage is the assignment to im-mediate care, hospitalization or evacua-tion of those casualties who are not criti-cally injured. This potentially displacesmore critically injured victims from medi-cal resources. The overtriage to GregorioMaranon hospital was estimated to be>50% with 0% undertriage. This trendof overtriage to nearby hospitals replicatesreported experiences in other inci-dents.3,10,11 Fortunately, the Madrid

trauma center rapidly adapted to the situ-ation. When medical resources are lim-ited, or not immediately available,overtriage can prove as deadly asundertriage for victims awaiting treat-ment.10 Even in Madrid, the triage mighthave proven disastrous if the attacks hadnot occurred in the early morning, whenthe full day staff of the hospital was arriv-ing and the operating rooms were pre-pared for the day’s first cases, but not yetoccupied.

There are numerous triage algo-rithms used in the management of blastvictims. Although the scoring systemsvary, each is designed to provide respond-ers with an easily remembered way toevaluate patients with high inter-rater re-liability. These systems provide a struc-tured framework for rescuers working ina chaotic environment. However, thereis no single approach, especially if “dirtybombs” complicate triage efforts follow-ing blast events.8 In these latter situations,an assessment of the safety and the expo-sure risk of rescue personnel along withthe risk of contamination of health careworkers and facilities must be consideredbefore rescue efforts commence.

Contrary to the common sense as-sumption, the great majority of survivorsof bombings are not critically injured. In

Data from the RAND®-MIPT Terrorism Incident database show that bombblast injuries account for 82% of all injuries caused by terrorists.1


part, this is due to the sobering fact thatthe immediate death rate from blast ex-posure tends to be high, ranging from50% - 99%. Those who do survive com-monly suffer soft tissue and musculoskel-etal injuries, most of which are non-criti-cal and non-life threatening. Critical in-juries occur in only 5% - 25% of survi-vors, and late deaths generally occur inthis severely injured group. Nineteen per-cent of all survivors with abdominal

trauma, 14% of all survivors with chesttrauma, and 10% of all survivors withtraumatic amputation or blast lung in-jury ultimately die, representing the bodysystem injuries with the highest specificmortality among survivors. However,these body system injuries are found inonly a small (2% - 5%) percentage of sur-vivors because most victims with theseinjuries died immediately before reach-ing medical care.12 In appropriate tri-

age, survivors with these injuries are rec-ognized early as having a high risk ofdeath.

These percentages have a direct im-pact on ongoing efforts to improve theaccuracy of field triage and optimizehealth care resource utilization followingblasts. Recent research into triage mark-ers based on a survey of soldiers in Iraqfound that sustained hypotension and thepresence of two or more factors, includ-ing three or more long bone fractures,penetrating head injury, and associatedfatalities are associated with increasedmortality.13 A review of suicide bombingsin Israel sought to define easily identifiedexternal injuries that correlated with thedevelopment of blast lung injury.14 In798 victims, significant associations(p<.001) with the development of blastlung were found between penetratingwounds to the head or torso, burnsgreater than 10% of the body surfacearea, and skull fractures. Additionally,victims in fully confined spaces, such asbuses, were more likely to suffer blast lungeffects. These findings provide rapid waysto identify patients who will likely requiremore intensive monitoring and resusci-tative efforts even before the clinicalmanifestations of pulmonary compro-mise become apparent.

Specifically, triage methodologiesmust take into account three primarycomponents as they interface either di-rectly or indirectly with the victim. Theseinclude the high-pressure shock frontand associated blast wave as well as anythermal components from the detona-tion. Classically, the injuries have beendivided into three categories (primary,secondary and tertiary). We have alsocome to also recognize several quaternaryelements.

Primary blast injury (PBI) occursas the shock front and blast wave movethrough the body. Differences in densi-ties of the body’s anatomical components(particularly at air/fluid interfaces) are sus-ceptible to spalling, implosion, inertialmismatches as well as pressure differen-tials. Spalling describes the forcible, ex-plosive movement of fluid from moredense to less dense tissues. This is com-mon in the lungs. Implosion relates toareas of gas that rapidly compress at thetime of shock front impact and then rap-idly re-expand after the front passes. This

Figure 2: Diagram of blast wave and associated components

In an open area, the overpressure that results from an explosion generally follows awell-defined pressure/time curve (“Friedlander wave”) with an initial nearinstantaneous spike in the ambient air pressure followed by a longer period of sub-atmospheric pressure.

Figure 3: Blast wave form


is frequently seen in the ear (tympanicmembrane) and intestine, where accel-eration/deceleration can cause tearing oforgan pedicles and mesentery when thereis an inertial difference between organstructures. Pressure differentials can oc-cur wherever there is a liquid/gas inter-face. Incompressible or fluid filled or-gans (e.g. vessels) may then be injuredwhen their fluid content is forced into aless compressible, adjacent structure.

Bomb detonation is the rapid chemi-cal transformation of a solid or liquid intoa gas. The gas expands radially outwardin the form of a high-pressure shock wavethat exceeds the speed of sound. Air ishighly compressed on the leading edgeof the blast wave creating a shock front.The body of the wave, including the as-sociated mass outward movement of air(sometimes called the “blast wind”) fol-lows this front.15 (Figure 2) In an openarea, the overpressure that results gener-ally follows a well-defined pressure/timecurve (“Friedlander wave”) with an ini-tial near instantaneous spike in the am-bient air pressure followed by a longerperiod of sub-atmospheric pressure. (Fig-ure 3)

Since the pressure/time curves varydepending on the local topography, (e.g.,the presence of walls/solid objects andwhether the blast is detonated indoors oroutside), knowledge of the physical pa-rameters of the explosive arena is criticalto triage analysis. In contained explosions,the blast wave can reflect off of and flowaround solid surfaces resulting in magni-fication of pressure up to 8 or 9 times,causing significantly greater injury.15,16

Although high-energy explosivessuch as TNT and nitroglycerin (NTG)are much more powerful than ordinarygunpowder, gunpowder’s high thermaloutput typically causes more burn inju-ries. In comparison, TNT and NTG arecleaner and more complete in combus-tion. They are, however, more devastat-ing because they create shockwaves ofhigher energy, causing other injuries be-sides burns.

This information is obviously impor-tant for medical teams evaluating blastinjuries. Likewise, medical teams shouldunderstand how the medium throughwhich the blast wave moves also impactsthe type and severity of injuries. Here, itshould be noted that any explosion has

the potential to be associated with nuclear,biologic or chemical contaminants, andthis should also remain a considerationfor healthcare givers until proven other-wise.17

Water, with its increased density, al-lows for faster propagation and a longerduration of positive pressure accountingfor increased severity in that environ-ment. The distance from the explosion’sepicenter is important, with pressurewave decay occurring roughly as the in-verse cube of the distance traveled.15,18

Since the most susceptible organs toprimary blast injury are the ears, lungs andgastrointestinal tract, tympanic membranerupture should also be used as a triagemarker for exposure to significant blastoverpressure. The lungs are moderatelymore resistant, but with enough energyexposure the air sacs can be disrupted andlocal capillaries can hemorrhage, leadingto emphysematous spaces and pneu-mothorax. The interstitial changes of blastlung can lead to Adult Respiratory Dis-tress Syndrome (ARDS). Notably, infil-trates can be seen on chest X-rays within90 minutes of the blast.19 In rare cases,air embolism of the vascular tree is thoughtto lead to sudden death.20 The gastrointes-tinal tract as a gas filled organ can be in-jured by implosion and rupture. Themucosal wall can become bruised. Shear-ing injuries can also occur, caused by ac-celeration/deceleration relative to moresolid, adjacent structures. Other organ sys-tems have varying degrees of response toinjury from primary blast and models havebeen developed to better study the over-all pathophysiological effects.15,20,21,22 Thelungs tend to be the predominantnonauditory system injured in most airblasts, whereas the gastrointestinal (GI)tract is more susceptible to underwaterblasts. Histochemical markers are beingsought to better diagnose and treat blastoverpressure injury.

Amputations are not common, butcan infrequently result from laceration byprojectiles formed secondary to the blast,which are significant as markers for po-tentially lethal injuries. These primarilyoccur through the shaft rather than asdisarticulations and are thought to be theresult of direct coupling of the blast waveinto the tissues. Although somewhat con-troversial, it is theorized that fracture re-sults from axial stress to the long boneand flailing of the extremity from the blastwind gas flow completes the amputa-tion.18,23 Improved knowledge in this areahas allowed for the development of moreeffective body armor.

Secondary blast injury results fromthe victim being struck by missiles thatare propagated by the explosion (shrap-nel). These might include the bomb’scasing or materials that have been inten-tionally imbedded into the explosive tocause wounding (primary fragmentation).Nails, screws, nuts and bolts seem to be afavorite of terrorists. Secondary fragmen-tation describes local material made air-borne by proximity to the explosion (e.g.glass). Most penetrating injuries causedby blast-driven projectiles should be con-sidered as contaminated andprophylaxed with antibiotics and tetanus.Small entry holes may be misleading anddecisions regarding which wounds to ex-plore and debride may be difficult. X-ray evaluation should be liberally used tolook for foreign bodies. There have beenreported instances of wounding by allo-genic bone fragments from suicide ter-rorists or other victims that have becomeimbedded in survivors. These cases re-quire special management with attentionto potential disease transmission.24

Tertiary injury stems from thevictim’s body being thrown as a projec-tile by the blast. This can result in frac-tures, head trauma and other blunt in-jury typically seen in the surviving popu-lation. Quaternary injury encompassesdamage from structural collapse or burnssecondary to the detonation. Crush,traumatic amputation, compartment syn-dromes in addition to other blunt andpenetrating injuries can be common se-quelae of structural collapse. Flash burnsto exposed skin can occur as a result ofthe thermal component of the detona-tion. Secondary fires can cause additionalburns as well as smoke inhalation.

Critical injuries occurin only 5% - 25% ofsurvivors, but latedeaths generally

occur in this severelyinjured group.


In conclusion, civilian physicians andsurgeons need increased understandingof blast injury, since early, accurate assess-ment—based on knowledge of blast me-chanics and patterns of blast injuries—has the potential to improve triage effortsand increase survivorship. Although in-jury from flying debris can be lethal, thevast majority of blast survivors are notcritically injured; thus, the challenge fac-ing the medical community is to effec-tively identify and treat those few casual-ties with severe injuries. To that end,information regarding the explosion type,physical environment, and typical factorscontributing to blast injuries all have adirect impact on triage evaluation. Giventhat most civilian medical professionalshave not been involved in true mass ca-sualty blast events, continued educationand advance planning will provide thecornerstone to coping with future blastevents.

REFERENCES1. MIPT Terrorism Knowledge Base >terrorist inci-

dents reports >Incidents by Tactics > Range:1/1/98–2/31/2005, http://www.tkb.org/IncidentTacticModule.jsp accessed May 5, 2006.

2. Mallonee S, Shariat S, et al. JAMA 1996;276:382-7.

3. Feliciano DV, Anderson GV, et al. Managementof casualties from the bombing at the CentennialOlympics. Am J Surg 1998;176:538-43.

4. Carley SD, Mackway-Jones K. J Accid Emerg Med1997;14:76-80.

5. Peral Gutierrez de Ceballos J, Turgano-Fuentes F,et al. Critical Care 2004;8:published on-line athttp//ccforum.com/inpress/cc2995.

6. Ryan J, Montgomery H. Terrorism and medicalresponse. NEJM 2005;353:543-5

7. Ciraulo DL, Frykberg ER, et al. J Trauma2004;56:1033-41.

8. Cone DC, Koenig KL. European J Emerg Med2005;12:287-302.

9. Gutierrez de Ceballos JP, Turegano Fuentes F, etal. Critical Care Med 2005;33(1 Suppl):S107-12.

10. Frykberg ER, Tepas JJ, Alexander RH. Am Surg1989;55:134-41.

11. Rodoplu U, Arnold JL, et al. J Trauma-InjuryInfection & Critical Care 2005; 59:195-20l.

12. Kluger Y. IMAJ 2003;5:235-40.13. Nelson TJ, Wall DB, Stedje-Larsen ET. J Am Coll

Surg 2006;202:418-22.14. Almogy G. Luria T. et al. Can external signs of

trauma guide management?: Arch Surg 2005;140:390-3.

15. Hull JB. J Audiovisual Media in Med1992;15:121-7.

16. Leibovici D, Gofrit ON, et al. J Trauma1996;41:1030-5.

17. Leibner ED, Weil Y, et al. J Trauma 2005;58:388-90.

18. Gans L, Kennedy T. Emerg Med Clin North Amer1996;14:301-25.

19. Caseby NG, Porter MF. Injury 1976;8:1-12.20. Jönsson A, Arvebo E, Schantz B. Intrathoracic

pressure variations in an anthropomorphicdummy exposed to air blast, blunt impact, andmissiles. 5th Symposium on Wound Ballistics1988;28, No.1 Suppl: S135-S131.

21. Irwin RJ, Lerner MR, et al. J Trauma1997:43:650-5.

22. Stuhmiller JH. Toxicol 1997;121:91-103.

Christopher T. Born, MD, FAAOS,FACS, is Professor of Orthopaedic Surgeryat Brown Medical School and Director,Orthopaedic Trauma Service, Rhode IslandHospital.

Ryan Calfee, MD, is a Fellow in Or-thopaedic Trauma at Rhode Island Hospi-tal.

Joann Mead, MA, is OrthopaedicTrauma Research Assistant, OrthopaedicTrauma Service, Rhode Island Hospital.

CORRESPONDENCEChristopher T. Born, MD, FAAOS,FACSOrthopaedic Trauma ServiceRhode Island HospitalMedical Office Center, Suite 2002 Dudley StreetProvidence, RI 02905Phone: (401) 457-1562E-mail: [email protected]


This CME activity is sponsored by Brown Medical School.

Target Audience: This enduring material is designed for physicians licensed in RhodeIsland.

Educational Objectives:1. Readers will know the new materials and new properties of biohybrid limbs.2. Readers will know the new advances in regenerative medicine [engineering tis-

sue and organ replacements] for limb trauma.3. Readers will describe the latest biomimetic prostheses.4. Readers will know the latest information on development of neuromotor pros-

theses.5. Readers will identify clinically meaningful improvement in the rehabilitation of

lower-limb amputees.6. Readers will know the facts about prevalence of blast injuries among civilians,

and triage protocols.

Needs Assessment: The incidence of massive civilian casualties, and injuries, from ter-rorist-activities and US engagement in warfare dates from the past 5 years. Physicianstoday are seeing more bombing-related limb injuries. This issue aims to update physi-cians on the kinds of injuries that are occurring, and the new treatment options thathave been developed, and are in the process of being developed.

Accreditation Statement: Brown Medical School is accredited by the AccreditationCouncil for Continuing Medical Education (ACCME) to provide continuing medicaleducation for physicians.

Credit Designation: Brown Medical School designates this educational activity for amaximum of 2 AMA PRA Category 1 Credits™. Physicians should claim credit commen-surate with the extent of their participation in the activity.

Faculty Disclosure: “In accordance with the disclosure policy of Brown Medical School aswell as standards set forth by the Accreditation Council for Continuing Medical Education(ACCME), all authors must disclose any and all commercial financial relationships within thepast 12 months. All authors have been advised that any recommendations involving clinicalmedicine must be based on evidence that is accepted within the profession of medicine asadequate justification for their indications and contraindications in the care of patients. Allscientific research referred to, reported, or used in the presentation must conform to thegenerally accepted standards of experimental design, data collection, and analysis.”

The following authors have disclosed the following significant commercial relationships:John P. Donoghue, PhD – Consultant: Cyberkinetics Neurotechnology Systems, Inc.;Michael G. Ehrlich, MD – Consultant and Grant Research Support: Biomimetics;Gerhard H. Friehs, MD – Consultant: Cyberkinetics Neurotechnology Systems, Inc.;Leigh R. Hochberg, MD, PhD – Grant Research Support: Cyberkinetics NeurotechnologySystems, Inc.; Hugh Herr, PhD – Stockholder: Walk, Inc.; Edith Mathiowitz, PhD –Consultant: Spherias; Grant Resarch Support: Spherias, Freedom II; John D. Simeral,PhD – Consultant: Cyberkinetics Neurotechnology Systems, Inc.

The following authors have disclosed that they have no significant commercial relationships:Roy K. Aaron, MD; Michael J. Black, PhD; Christopher T. Born, MD, FAAOS. FACS; RyanCalfee, MD; Deborah McK. Ciombor, PhD; Michael Lysaght, PhD; Joann Mead, MA, JeffreyR. Morgan, PhD; Arto V. Nurmikko, PhD; Linda Resnik, PhD, PT, OCS.

Acknowledgement: The material contained in this issue is a result of the editorial workby Roy K. Aaron, MD, guest editor. The opinions expressed herein are those of theauthors and do not necessarily reflect the views of the sponsors, publisher or the plan-ning committee.

To obtain credit: Submit answer sheet and $25 fee to Office of Continuing Medical Educa-tion, Brown Medical School. Respondents must score 70% or higher for credit. Statementsof credit will be mailed within 6 to 8 weeks following the receipt of the answer sheet.

PRINT OR TYPE

Name _____________________________ Degree ______Address ________________________________________City, State, Zip __________________________________Phone ( ) __________________________________Fax ( ) ______________ e-mail _________________Hospital __Private Practice __Resident __Intern __Other

CME Background Information�

CME Registration FormFor credit to be received, please mail your registration with $25

fee and answer sheet to Office of Continuing Medical Education,Brown Medical School, 171 Meeting Street, Box G-B495, Provi-dence, RI 02912.

Keep a copy for your files. Compare them with the correct an-swers, which will be made available upon request, and receipt of sub-mission requirements.

Deadline for Submission: June 30, 2007

EvaluationPlease evaluate the effectiveness of the CME activity on a scale of 1 to 5 (1 being poor, 6 being excellent) by circling your choice.

1. Overall quality of the CME activity 1 2 3 4 5

2. Content 1 2 3 4 5

3. Format 1 2 3 4 5

4. Faculty 1 2 3 4 5

5. Achievement of education objectives* I know the new materials and new properties of biohybrid limbs. 1 2 3 4 5* I know the new advances in regenerative medicine [engineering tissue

and organ replacements] for limb trauma. 1 2 3 4 5* I can describe the latest biomimetic prostheses 1 2 3 4 5.* I know the latest information on development of neuromotor prostheses. 1 2 3 4 5* I can identify clinically meaningful improvement in the rehabilitation

of lower-limb amputees. 1 2 3 4 5* I know the facts about prevalence of blast injuries among civilians,

and triage protocols. 1 2 3 4 5

6. Will you change the way you practice based on what you learned in this activity? Yes or No

If Yes, how? _______________________________________________________________

7. This activity was presented without evident commercial bias or influence.

_______ I Agree _________ I Disagree

If you disagree, please explain. __________________________________________________

Additional comments and/or suggested topics for CME activities. _______________________

__________________________________________________________________________

Payment methods: Choose A or B

A. ___check enclosed, payable to Brown University CME

B. ___charge to my credit card___VISA ___Master Card___American Express

Account number:

____________________________

Expiration date:_______________

Cardholder’s name:

____________________________(please print)

Cardholder’s signature____________________________

And mail with answer sheet toCME office, Brown Medical School171 Meeting Street, Box G-B495Providence RI 02912or fax to 401-863-2202


1. Which of the following statements about theconcept of the biohybrid limb is not true:a. Current examples of biohybrid limbs

include bone and joint replacements,engineered skin, osseointegrated tran-scutaneous implants, cardiovasculargrafts, and neuro-prosthetics.

b. Biophysical properties result from theinterface between non-biological andbiological tissues.

c. Titanium joint replacements have raisedserious concern with researchers becauseof the complications that result from theintegration of titanium with bone.

d. Conceptualizing a limb as a biohybridorgan can free the researcher from con-straints imposed by certain limitationsof biomaterials.

2. If researchers succeed in developing an envi-ronmental seal by integrating skin and der-mis with titanium, they could potentially ac-complish which one of the following:a. A decrease in percutaneous contamina-

tionb. A decrease in titanium oxide surface filmc. An increase in growth factor secretiond. An increase in marsupialization

3. Which of the following provides the theo-retical basis for using growth factors tostimulate endogenous repair and to facili-tate cell-mediated engineered repair:a. Unique biophysical properties result

from the interface between non-biologi-cal and biological tissues.

b. Many of the same signaling moleculesthat regulate cartilage development inembryogenesis are re-expressed in post-natal life during tissue growth and re-pair.

c. Synovium has a demonstrated propen-sity to undergo chondrogenesis andcontains a mixed population of cellsthat respond differently to variousgrowth factors.

d. TFG-β1, when combined with IGF-1,

can dramatically inprove chondrogen-esis compared to the supplementationof TFG-β

1 alone.

4. Since delayed bone union complicates re-habilitation and restoration of limb func-tion after distraction osteogenesis, tissue en-gineering research is exploring all of the fol-lowing avenues except:a. Progressive weight-bearingb. Using growth factors and biopeptides

to stimulate healingc. Low intensity ultra sound radiationd. Neuro-motor bone implants

5. The most radical improvement in pros-thetic knee joint technology in the 1970swasa. A decrease in percutaneous contami-

nationb. Mechanical power generationc. The Series Elastic Actuatord. Active variable damping

6. Which of the following is not a problemfor lower limb amputees who are usingcommercially available prosthetics (i.e.,prosthetics that are not yet capable of fullyrestoring natural limb function).a. Increased osseoperceptionb. Difficulties maintaining balance when

walking, especially over rough terrainc. Impaired metabolic economy and re-

sultant undue fatigued. Lack of direct response to amputee in-

tention (i.e., when an obstacle ap-pears in a pathway or the intentionto turn right or left)

7. Neuromotor prosthesis (NMP) technol-ogy has the potential toa. accumulate, synthesize and store data

about the user’s usage, includingmetabolic rates, gait patterns and vari-able damping rates

b. enable direct two-way interaction be-tween the human brain and a me-chanical prosthesis

c. stimulate cortical “spikes” that will re-lease naturally present growth factorsto catalyze chondrogenesi.

d. decode cortical “spikes” that willstimulate endogenous repair and/orfacilitate cell-mediated engineeredrepair

8. Which of the following statements aboutthe miniaturized brain implantable NMPtechnology now under development is nottrue:a. It is compatible with the longer term

goal of connecting motor cortex sig-nals to external prosthetic devices.

b. It is compatible with the longer termgoal of connecting motor cortex sig-nals to muscle nerves via a fiber opti-cal network within the body.

c. It is capable of providing direct braincontrol of artificial limbs for ampu-tees.

d. It is flexible and scalable to allow trans-mission of large amounts of neural in-formation from the cortex to assistivetechnologies (such as a prosthesis, awheel chair, or a computer cursor).

9. For assessment measures, minimum de-tectable change (MDC) is defined asa. the minimum amount of change that

exceeds measurement errorb. the threshold at which an individual

has experienced a clinically relevantchange.

c. the ability of an instrument to detectclinical change as judged by an exter-nal criterion.

d. a single value applicable across all pa-tients.

10. Which of the following does not createproblems for the assessment of amputeeprosthetic satisfaction, quality of life andmobility:a. Some assessment tests lack the psy-

chometric properties that enablethem to detect change on the indi-vidual level.

b. Individual self-report assessment mea-sures do not currently exist for am-putees.

c. Some assessment tests in this realmhave shown strong floor and ceilingeffects.

d. Many current assessment measuresthat work well with large groups donot work on individuals or smallgroups.

11. In assessing blast victims (during triageand emergency room screening) medicalpersonnel should know that victims of ab-dominal trauma, chest trauma and lunginjurya. are likely to be fewer when the blast

takes place underwaterb. are likely to be fewer when the blast

takes place in a confined spacec. have the highest rates of mortalityd. have the lowest rates of mortality

12. According to the essay on blast injuries,in comparison with ordinary gunpowder,TNT and nitroglycerin (NTG)a. are less clean and less complete in com-

bustionb. have a lower thermal output (which

means that victims of gunpowderblasts will typically have fewer burninjuries).

c. are more devastating because they cre-ate shockwaves of higher energy, caus-ing other injuries besides burns.

d. are more common in blast explosions

TTTTTHEHEHEHEHE B B B B BIOHYBRIDIOHYBRIDIOHYBRIDIOHYBRIDIOHYBRID L L L L LIMBIMBIMBIMBIMB: CME Q: CME Q: CME Q: CME Q: CME QUESTIONSUESTIONSUESTIONSUESTIONSUESTIONSPlease circle the single correct answer for each of the questions below:


Using the Comprehensive Clinical Approach to Older PatientsAna C. Tuya, MD, and Richard W. Besdine, MD

GERIATRICS FOR THEPRACTICING PHYSICIAN

An 84-year-old woman comes to your officefor routine follow up. Her problem listincludes osteoarthritis and hypertension.She has no specific complaints on presen-tation, but you note she is using a cane forthe first time since you’ve known her. Onspecific questioning, she reports severalweeks of worsening of her chronic lowerextremity edema, and increased difficultyclimbing stairs and walking long distances.In fact, her daughter has begun doing herfood shopping. She says she’s doing bet-ter with the cane, and her left knee pain isbetter since she started using over thecounter Advil about one month ago.

This patient illustrates common dilem-mas presented by complicated older adultswith functional decline of unknown etiol-ogy in the face of multiple co-morbidities.Caring for the older adult requires the skillsof a good physician and of a talented de-tective; disease in old age can present with-out classic or typical findings. The aging ofthe baby boomer generation, along withincreases in life expectancy and medical ad-vances, are producing stunning increasesin the population of older Americans—over 65, over 75 and especially those over85. Projections from the US Census Bu-reau estimate approximately 90 millionAmericans over the age of 65 and almost20 million persons over 85 by the year 2050.Knowing some of the key principles of careand treatment for older adults will be use-ful for all physicians and practitioners, re-gardless of specialty or patient population,excluding only pediatricians. The agingimperative brings with it the challenge andexcitement of caring for a complex patientpopulation, in whom atypical presentationsabound, and where small interventions of-ten bring large and rewarding results forboth patient and physician.

The goal of this column is to provideclinicians with 1) case-based learning andreinforcement of basic principles of Geri-atrics, 2) updates on new treatment optionsfor conditions of interest, 3) tools for use indaily practice, and 4) resources for furtherlearning and for teaching students. Com-munity referral sources, web-based teach-

Division of Geriatrics, Department of Medicine, Brown University • Quality Partners of RI EDITED BY ANA C. TUYA, MD

cog) and assessment of social supports andliving situation.

The activities of daily living (ADL)include toileting, feeding, dressing, groom-ing, walking, and bathing. The instrumen-tal activities of daily living (IADL) includetelephone use, shopping, food preparation,housekeeping, laundry, transportation, andmedication and finance management. Inadults 65-74 years old, 15% describe oneor two ADL dependencies, and 11% de-scribe needing assistance with IADL. Forthose 85 and older, the percentages increaseto 13% requiring assistance with IADL and27% with ADL decline1. Performing anUp and Go test (rise from a chair, walk 10feet, turn, walk back and sit) can provideuseful information about fall risk and bal-ance. If the patient takes longer than 9 sec-onds to perform the test, falls risk is in-creased; such patients would benefit fromphysical therapy assessment for interven-tions. If time does not permit formalmeasurement of the test, then simply watch-ing the patient walk, such as when goingfrom a chair to the exam table is also useful.

Depression screening is recom-mended; although not more common withage, under-reporting and much lower de-tection rates are reported. One-quarter ofolder adults acknowledge depressive symp-toms, but only 1-9% meet DSM criteriafor major depression2. The geriatric depres-sion scale has a short form of 15 questionsthat can be administered quickly. Impairedpsychosocial function predicts morbidity,mortality and functional decline. Cogni-tive assessment should also be performedat least yearly and during any new visit. TheFolstein MMSE can be used, but manypractitioners are using the Mini-Cog (three-item recall and clock drawing) as a quickerscreen. Asking about other losses of func-tion is also useful; e.g., incontinence, hear-ing, nutrition. Older patients may assumethat symptoms in these domains are part of“normal aging,” and often do not complain.The above tools collect important informa-tion about an older adult’s risks for func-tional decline and any need for alterationin living situation; their use also detects func-

ing tools and learning resources will be pro-vided. Topics will include outpatient careand prevention, nursing home medicine,and inpatient acute care.

Among healthy older adults, homeo-stasis is maintained in fine balance, just asin younger persons. The crucial differenceis that changes in organ reserve, due to ag-ing alone, are common, and lead to re-stricted capacity to maintain that homeo-stasis when stressed. Sometimes called“homeostenosis” (a made up but vividword), the concept is critical to under-standing older persons. Only modest se-verity of physical illness, drug toxicity ortrauma often results in catastrophic de-clines, leading to a cascade of seeminglyunrelated problems (pneumonia present-ing with confusion, falling, urinary incon-tinence and loss of self-care capacity). Insuch circumstances, recognition of theunderlying trigger is challenging, especiallyif evaluation is limited to the organ withobvious symptoms – brain in confusionalstates, urinary tract for incontinence, andmotor system for falls. Finally, multiple co-morbid conditions, changes inpharmaoco-kinetics and pharmaco-dy-namics, and the changes of pure aging leadto additional levels of complexity.

Hence, the tool of comprehensive ge-riatric assessment (CGA) has been devel-oped to provide systematic assessment of theolder adult to detect subtle changes, and toavoid missing important areas for interven-tion. The goal of CGA is to create amultidisciplinary care plan that will antici-pate problems and prevent illnesses andfunctional decline; the ultimate goal is pres-ervation of independence. Since CGA canconsume a full new patient visit, quickscreening (5 minutes) can be used to iden-tify any needs for further assessment. CGAand screening can be especially useful whenevaluating a new patient or when a newstressor, diagnosis, or transition in level ofcare has occurred. The basic componentsof CGA include assessment of physicalfunction (ADL, IADL, Timed Up and Gotest, and balance testing), affect (geriatricdepression scale), cognition (MMSE, Mini-


tional decline early, allowing intervention before harm occurs.Now let’s return to our patient; she presents with new func-

tional decline, triggering CGA. Is this decline due to worsen-ing lower extremity edema, or is it due to the recent flare in herleft knee osteoarthritis? Did Advil contribute? Additional his-tory indicates that she remained independent until a monthearlier, when her knee pain flared. Prior to this flare, she usedthe bus to go shopping, did her own housework and was ableto climb steps without limitation. After the knee pain wors-ened, she began using Advil daily. Her daughter took overgrocery shopping, and the patient began using her deceasedhusband’s old cane for support.

CGA spotlights the functional decline, which seems relatedto her increased venous stasis edema. While observing the pa-tient move toward the exam table, you notice that her cane is toolong for her—the handle at least 6 inches higher than the ulnarstyloid of her arm when it is fully extended perpendicular to theground. In addition, she uses the cane with the left hand—canes should be held in the arm on the side opposite the painfulor weak lower extremity. You and the patient agree to stop theAdvil, since it seems to be contributing to her fluid retentionand increased edema, and try Tylenol around the clock. Sheagrees to physical therapy, where a new cane is fitted, she is in-structed in its use and strengthening exercises are begun. Twoweeks later, she reports that she no longer needs the cane and isable to use the bus to do her own shopping again. The edemahas significantly improved as well, and she is thrilled to have re-gained her ability to live independently.

A parallel ending to this case could be described; imaginethe same patient presenting to her physician’s office with im-proved osteoarthritic pain on Advil, and ambulation with thecane. A physician not familiar with CGA might have overlookedthe improper fit of the cane and the significance of the func-tional decline, and no evaluation would have occurred. Withcontinued Advil use, a different scenario is plausible. The pa-tient remained stable for several months, but had progression ofher edema and further restricted her activities. She started torely on her daughter for help with housework and cooking. Oneevening she developed shortness of breath and orthopnea andcalled rescue. She was admitted for fluid retention and CHF,and treated with Lasix and oxygen, with improvement. How-ever, while in the hospital she developed delirium secondary toelectrolyte imbalance and dehydration from excess diuretics, felland fractured her left hip. Surgery was successful, and she wasdischarged to a nursing home for rehabilitation after her de-lirium cleared. Because she never regained pre-fracture mobil-ity, and because she could no longer manage her medicationsindependently due to lingering cognitive deficits, she became apermanent resident of the nursing home.

The failure to recognize the significance of a seemingly smalldecline in function, and to anticipate its possible consequences,led to the uninterrupted cascade of decline, resulting in loss ofindependence and further co-morbidities with increased mor-tality risk. Delirium and hip fracture both carry substantial in-creases in mortality. The mortality rate for delirious hospitalizedpatients ranges from 22-76%, and the increased risk persists forup to a year3. One-year mortality for hip fracture is 15-25% inwomen, and higher in men. Most significantly, this version ofour patient’s story ends with her permanent placement in a nursinghome—an outcome greatly feared by most of us.

The goals of geriatric care are to promote successful aging,

to prevent and reduce disability, and to preserve independence.CGA provides a toolkit that can highlight disability early andgenerate a comprehensive multidisciplinary care plan that willanticipate and prevent clinical catastrophes and interrupt thecascade of decline. The principles learned from assessment re-search can be implemented in the busy office practice and canbe streamlined to fit the physician’s needs. Take home question-naires, pre-visit forms, and home assessments by occupationaltherapy or nursing can gather many of the elements for assess-ment and care planning when indicated by the office evalua-tion. Finally, community resources can be of tremendous assis-tance to a busy practitioner with limited support. The followingare sources of referral and on-line resources for the tools allow-ing you to perform CGA on a routine basis.

RESOURCES1. Resources for Geriatric Education: Web based toolkit with

relevant screening tests, instructions on assessment andscoring, and the necessary forms in PDF links, articlesand useful websites for practitioner support.http://www.chcr.brown.edu/toolkit.htm

2. AGS-sponsored pocket text for Geriatrics, now availableas PDA-based and on-line.http://www.geriatricsatyourfingertips.org

3. Division of Geriatrics Faculty 444-5248

4. East Avenue Geriatrics Practice for referrals 728-7270

5. Reynolds Project Resource Center for Geriatrics Educa-tion (RCGE) 863-3211

6. American Geriatrics Societyhttp://www.americangeriatrics.org

REFERENCES1. Burton L, Kasper J. Demography. In: Pompei P, Christmas C, Counsell S, et.al. eds.,

Geriatric Review Syllabus 6th Edition, NY: American Geriatrics Society, 2006: 5-7.2. Raj A. Depression in the elderly. Postgrad Med 2004; 115:26-423. Gleason O. Delirium. Am Fam Phys 2003; 67: 1027-344. Wieland D. Comprehensive Geriatric Assessment. Cancer Control 2003; 10: 454-62.

Ana C. Tuya, MD, is Assistant Professor, Division of Geriat-rics, Brown Medical School.

Richard W. Besdine, MD, is Professor of Medicine and Di-rector, Division of Geriatrics, Brown Medical School.

CORRESPONDENCEAna C. Tuya, MD593 Eddy Street APC 424Providence RI 02903email: [email protected]

8SOW-RI- GERIATRICS -012007THE ANALYSES UPON WHICH THIS PUBLICATION IS BASED wereperformed under Contract Number 500-02-RI02, funded bythe Centers for Medicare & Medicaid Services, an agency ofthe U.S. Department of Health and Human Services. The con-tent of this publication does not necessarily reflect the viewsor policies of the Department of Health and Human Services,nor does mention of trade names, commercial products, ororganizations imply endorsement by the U.S. Government.The author assumes full responsibility for the accuracy andcompleteness of the ideas presented.


Birth Defects In Rhode IslandSamara Viner-Brown, MS, and Meredith Bergey, MSc, MPH

Birth defects are structural abnormalities that affect the devel-opment of organs and tissues of an infant or child. These abnor-malities may be identified during pregnancy, at birth or follow-ing birth. Possible causes or contributing factors to birth defectsinclude genetic factors, environmental pollutants, occupationalhazards, dietary factors, infections, medications, and personalbehaviors.1 In both the United States and Rhode Island, birthdefects are a leading cause of infant mortality and contribute tochildhood illness and disability. However, early recognition andresponse to birth defects may often prevent more serious effects.

Rhode Island began developing a birth defects surveil-lance system in 2000, with funding from the Centers for Dis-ease Control and Prevention (CDC). During 2003, the RhodeIsland General Assembly enacted legislation (Rhode Island Gen-eral Law 23-13.3) requiring the development and implemen-tation of a birth defects reporting, surveillance and informa-tion system by the Rhode Island Department of Health. TheRhode Island Birth Defects Program, created in response tothis mandate, is designed to track the prevalence of birth de-fects among children ages 0 – 5 in Rhode Island and collectinformation on the characteristics of those children and theirparents, assure that those children and their families receiveappropriate services and referrals, and identify and close gapsin services for families of children with birth defects. This re-port presents selected summary data from the Birth DefectsProgram for the years 2001-2005.

METHODSData on birth defects in the Rhode Island population are

collected in two ongoing data sources maintained by the De-partment of Health: birth certificate data collected by the Of-fice of Vital Records and hospital discharge data collected by theCenter for Health Data and Analysis. Birth certificate data in-clude a wide variety of information on the characteristics of thechild, parent, and birth experience, but may not capture all birthdefects and does not identify birth defects at the level of detail inthe International Classification of Diseases coding system (ICD-9-CM).2 Hospital discharge data include a record for nearlyevery birth occurring in the state and code all recorded birthdefects in ICD-9-CM, but collect few data items on the charac-teristics of the child and parents. Therefore, the Birth DefectsProgram uses hospital discharge data to identify newborns withbirth defects and links their hospital records with their birth cer-tificate records. In addition to case identification through thehospital discharge database, the Birth Defects Program is work-ing with Women & Infants Hospital, Rhode Island Hospital,and Hasbro Children’s Hospital to obtain additional cases ofbirth defects and information on services provided to families ofchildren with birth defects. To determine whether children withbirth defects receive appropriate preventive services, the BirthDefects Program links children identified with birth defects to

Rhode Island’s integrated child health information system,KIDSNET. Since KIDSNET maintains information from tenprogram databases, children who are not receiving services canbe identified and provided outreach and referrals.

RESULTSAmong the 61,870 Rhode Island babies born in the state’s

maternity hospitals during 2001-2005, hospital discharge dataindicate that 3,510 (5.7%) had at least one birth defect. Byyear, the number of newborns with birth defects ranged froma low of 691 in 2001 to a high of 720 in 2005. Overall, thestatewide prevalence rate per 10,000 births for birth defectshas remained stable over the past five years, varying within arange of only 7% around the five-year average rate of 567 ba-bies per 10,000. (Figure 1)

Birth defects have been reported in all organ systems amongRhode Island newborns during 2001-2005. (Table 1) The mostfrequent birth defects are those related to the cardiovascular sys-tem, where one in 40 babies are born with a cardiovascular de-

RHODE ISLAND DEPARTMENT OF HEALTH • DAVID GIFFORD, MD, MPH, DIRECTOR OF HEALTH EDITED BY JAY S. BUECHNER, PHD

Figure 1. Newborns with birth defects per 10,000 live births,Rhode Island, 2001-2005.


fect. Also common are birth defects affecting the musculoskel-etal and integumentary systems and the genitourinary system.

The prevalence rate for birth defects varies with maternal char-acteristics. Babies born to older women (ages 35 or greater), womenwith less than a high school education, single women, women withpublicly funded health insurance, or women of color, are at a higherrisk for birth defects. (Figure 2) During 2005, the birth defectsrate among women aged 35 or greater was 686.4 compared to520.5 among women aged less than 20. Similarly, the birth de-fects rate among women with less than a high school education(669.0) was 1.25 times the rate among women with more than ahigh school education (536.5). Single women (774.0) were nearlytwice as likely to have a baby with a birth defect than marriedwomen (453.6). Women who were insured through public pro-grams such as RIte Care and Medicaid were also more likely tohave a baby with a birth defect (661.1) than women insured bycommercial or private providers, such as Blue Cross and UnitedHealthcare (523.1). Black/African American women were more

likely to have a baby with a birth defect(748.7) than White women (560.6). Birthdefect rates were also higher among thosewho resided in the core cities, including Cen-tral Falls, Newport, Pawtucket, Providence,West Warwick and Woonsocket (626.7 per10,000 newborns) than those who lived inthe rest of the state (556.3).

Data indicate that among Rhode Islandchildren born in state during 2004, a higherproportion of children with birth defects werescreened for lead poisoning, were enrolled inthe state’s WIC and Early Intervention pro-grams, and received home visits compared tochildren without birth defects. (Figure 4)

DISCUSSIONOver the last five years, 5.7% of newborns

in Rhode Island, or approximately 700 peryear, have been diagnosed with birth defects.Nationally, the reported prevalence rate ismuch lower, at 3.0%.3 However, because thereare no national uniform standards for case as-

certainment, it is difficult to compare rates across states. For ex-ample, some state registries use active surveillance (i.e., a case findingprocess where cases are identified at multiple data sources and in-cludes identifying potential birth defect cases, medical record ab-straction and follow-up), while others use passive surveillance (i.e.,wait for data to be submitted to the program by limited data report-ing sources), and still others use a combination of passive and activesystems.4 Also, some states limit their registries to live birth outcomeswhile others may also include fetal deaths. Although Rhode Islandis working to make its case ascertainment system an active one, thesystem currently is passive and does not include data on fetal deaths.

Once birth defects cases are identified, the Rhode IslandBirth Defects Program works to assure that these children andtheir families receive appropriate services and referrals. TheProgram also has been conducting focus groups, interviews andsurveys with families to learn about their experiences with thehealth care system and to determine any gaps in or barriers tothe system. This information will be used to develop strategiesthat will help link families to follow-up and treatment services,which hopefully, will lead to a reduction in disparities.

Samara Viner-Brown, MS, is Chief, Data and Evaluation,Division of Family Health, Rhode Island Department of Health.

Meredith Bergey, MSc, MPH, is Epidemiologist, Birth De-fects Program, Division of Family Health, Rhode Island Depart-ment of Health.

REFERENCES1. Rhode Island Birth Defects Program, Rhode Island Department of Health.

Birth Defects Data Book. 2005. http://www.health.ri.gov/family/birthdefects/birth-defects-databook.pdf

2. Public Health Service and Health Care Financing Administration. Interna-tional Classification of Diseases, 9th Revision, Clinical Modification, 6th ed. Wash-ington: Public Health Service, 1996.

3. http://www.cdc.gov/ncbddd/bd/facts.htm4. National Birth Defects Prevention Network. Guidelines for Conducting Birth

Defects Surveillance. June 2004.

Figure 2. Newborns with birth defects per 10,000 live births, by selected maternalcharacteristics, Rhode Island, 2005.

Figure 3. Newborns receiving selected preventive services,by diagnosis of birth defects, Rhode Island, 2004.



A Nervous Assortment of Words�

Physician’s Lexicon

The histologic structure of the centralnervous system was the last of the major or-gans to be clarified. Anatomists had clearlyportrayed the cellular architecture of mostof the internal organs of the body by themiddle decades of the 19th Century. Thebrain, however, was refractory to the earlyhistologic stains and was therefore thoughtof as an ill-defined syncytial soup, lackingin discreet cellular membranes. This viewprevailed until the meticulous microscopicstudies of Golgi, and particularly Cajal,both of whom used metallic impregnationstains to demonstrate the cellular compo-nents within this mysterious “soup.” Cajalthen defined the anatomy of the neuron,its numerous cytoplasmic extensions, its syn-aptic intimacies and from its linear configu-ration he then inferred the unidirectionalcharacter of its signaling capabilities.

The root, neuro- [as in neuron] comes

from a Greek word meaning sinew or ten-don; and from a still earlier term meaningvigor. The derivative Latin, nervus, becamethe direct source of the many English wordspertaining to neural activity [neuroglia, neu-rology, neurosis, neurotransmitter, neuras-thenia, etc.]

The word, nucleus, is derived from theLatin, nuculeus, meaning little kernel, whichin turn is from the Latin, nucis, meaning nut.

Axon, the major efferent limb of theneuron, is from a Greek word meaning axle.Cognate words in English include axis, axil[the angle between a leaf and its branch] andaxillary [a Latin term meaning armpit, refer-ring to the angle formed by the arm andlateral thorax.] And, via the Anglo-Saxontongue, the words, aisle, aileron and alar.

Dendrite is also a derivative of a Greekword, the dendro- root meaning tree, branchor root. The term appears in such words as

rhododendron [red roots], dendrology [thestudy of trees], dendrolite [fossil plants; liter-ally, a stone tree], oligodendroglia [glial cellswith a paucity of branches] and epidendrum[a genus of tree orchids.]

Synapse is derived from the Greekword, synaptein, meaning to bind together.The syn- prefix means with or together andappears in words such as synarthrosis [fusedjoint], synchronize, syncytium [a joining ofcells], syndrome,[ a running together],synod, syndicate, synonymous, synergy andsyncope [in medicine, a fainting spell; inmusic, a displacement of a beat.]

Neuroglia, the non-neuronal cellularcomponents of the central nervous system,is a word based upon a Greek term mean-ing sticking together or glue. Cognate wordsinclude glioma, gliosis, and glioblastosis.

– STANLEY M. ARONSON, MD

Diseases of the HeartMalignant Neoplasms

Cerebrovascular DiseasesInjuries (Accidents/Suicide/Homicde)

COPD

Number (a)203194

352662

Number (a) Rates (b) YPLL (c)2,848 266.2 4511.02,312 216.1 6,331.5**

474 44.3 702.5421 39.4 6,262.0522 48.8 467.5

Reporting Period

12 Months Ending with January 2006January2006

UnderlyingCause of Death

Live BirthsDeaths

Infant DeathsNeonatal Deaths

MarriagesDivorces

Induced TerminationsSpontaneous Fetal Deaths

Under 20 weeks gestation20+ weeks gestation

Number Number Rates1,278 13,089 12.2*

822 9,759 9.1*(7) (97) 7.4#(4) (76) 5.8#

928 7,171 6.7*265 3,114 2.9*392 4,775 364.8#

43 994 75.9#(41) (941) 71.9#(2) (53) 4.0#

Reporting Period12 Months Ending with

JuLY 2006JuLY2006

Vital Events

Rhode Island MonthlyVital Statistics Report

Provisional OccurrenceData from the

Division of Vital Records

(a) Cause of death statistics were derived fromthe underlying cause of death reported byphysicians on death certificates.

(b) Rates per 100,000 estimated population of1,069,725

(c) Years of Potential Life Lost (YPLL)

Note: Totals represent vital events which occurred in RhodeIsland for the reporting periods listed above. Monthly pro-visional totals should be analyzed with caution because thenumbers may be small and subject to seasonal variation.

* Rates per 1,000 estimated population# Rates per 1,000 live births** Excludes 1 death of unknown age

RHODE ISLAND DEPARTMENT OF HEALTH

DAVID GIFFORD, MD, MPHDIRECTOR OF HEALTH EDITED BY COLLEEN FONTANA, STATE REGISTRAR

V ITAL STATISTICS


a d v e r t i s e m e n t


NINETY YEARS AGO, JANUARY 1917Frank F. Peckham, MD, in “Lateral Curvature of the Spine

– An Original Method of Treatment,” discussed physiologicaland mechanical treatments; e.g., permanent jackets.

Harry S. Bernstein, MD, in “Initial Experiences in theOffice of the State Pathologist,” described advances made inthis new office, created by the state legislature in 1914. Forinstance, the staff initiated postage-delivery of specimens: “a 5cents stamp covers the postage of a specimen of sputum in itsappropriate container.” The state collected specimens threetimes daily from a post office box. Data from the office in-cluded 126 stool specimens examined for typhoid bacillus inthe past 2 years; 4 tested positive (2 on different occasions fromthe same person). In the first year, the laboratory analyzed 99specimens for diagnosis of malaria; 6 were positive.

William L. Harris, MD, in “Pelvic Appendix,” cautioned:“…a ruptured, post-colic appendix, or a gangrenous appen-dix within the true pelvis, frequently yields no physical signswhatever.”

An Editorial, “Campaign Against Wood Alcohol,” urgedreaders: “See to it that your barber uses only the best toiletarticles, and that the ginger ale you drink is one that does notcontain this poison.”

FIFTY YEARS AGO, JANUARY 1957Merrill C. Sosman, MD, Samuel A. Levine, MD, and J.

Engelbert Dunphy, MD, all faculty at the Harvard MedicalSchool, had presented a panel discussion “A Brigham X-RayConference: Medical and Surgical Cases,” at the [October1956] Interim Meeting of the RI Medical Society. The Jour-nal reprinted the discussion.

Michael G. Pierick, MD, and Taras Hanusheusky, MD,contributed “Chronic Arterial Insufficiency and Fatal Anaphy-lactoid Transfusion Reaction.” A 15 year –old girl, who hadhad ankylosing rheumatoid arthritis for the previous 5 years,was admitted to Our Lady of Fatima Hospital for rehabilita-tion. Several years of adrenal steroids had relieved her pain,but left her with knee deformities, moon facies, lethargy, and“depressive type of personality change.” She moved from bedto wheelchair. The treatment goal was to increase her mobility.After 3 weeks of a gradual decrease in prednisone, she had noill effects; she lost 12 pounds; and her spirits improved. Onthe 14th day after the end of all cortisone therapy, she receiveda supportive whole blood transfusion of 500cc of Group A,,RH+ blood. The patient died of a pulmonary edema, eighthours after the onset of the reaction.

TWENTY-FIVE YEARS AGO, JANUARY 1982Charles E. Millard, MD, in President’s Corner, contrib-

uted “Health Planning May Be Dangerous to Your Health.”He objected to proposals to reduce the number of hospitalsand nursing homes, in light of the high occupancy rates forthose institutions in RI.

An Editorial, by Seebert J. Goldowsky, MD, “NursingHome Bed Information System,” praised the recent bed clear-inghouse in Rhode Island, organized by the Hospital Associa-tion of RI, the RI Medical Society, the RI Professional Stan-dards Review Organization, the State Department of Socialand Rehabilitative Services, and the State Department ofHealth.

Toussaint A. Leclerq, MD, FACS, contributed “EpiduralStimulation for Pain Control in the Failed Disc Syndrome.”He noted: “Success is possible in half of the cases if carefullyselected.”

Constantine P. Pagones, MD, and Paul C. Hessler, MD,in “Recurrent Pacemaker Electrode Displacement in The RightAtrium With Capture,” noted: “Improved leads reduce theprevalence of this complication.”

�

�

�

�VOLUME 1 PER YEAR $2.00NUMBER 1 SINGLE COPY, 25 CENTSPROVIDENCE, R.I., JANUARY, 1917

The Official Organ of the Rhode Island Medical SocietyIssued Monthly under the direction of the Publications Committee

To find out more, or to speak to an Army Health CareRecruiter, call 800-784-8867 or visithealthcare.goarmy.com/hct/50


AUTHORSAboagye-Kumi, Mose 362 [abs]Abbott, David 195Abrantes, Ana M. 169Aliotta, Jason M. 363[abs]Amick, Melissa M. 130Appel, Jacob M. 223Arcand, Arthur A. 285Aronson, Stanley M. 5,43,53,85,89,

115,125,153,157,189,193,225,229,248,261,265, 292,297,324,329,356, 361,384,389,420

Atalay, Michael K. 14

Baird, Todd B. 109Bartholomew, Kristin 91Bauer, Johannes H. 314Bell, Rose 299Berkman, Julia M. 94Bert, Arthur 20Blum, Andrew S. 127Borkan, Jeffrey M. 267Brady, Cathie 187Braun, Lundy 316Bridges, Carrie 347Brodsky, Jennifer 379Brown, Richard A. 169Brumbaugh, Matthew 312Buechner, Jay S. 41,81,110, 183,415Buxton, Alfred E. 41

Cain, Rachel 215Caldamone, Anthony A. 365,370Campanile, Chris 400Carpenter, Linda L. 134,137,180Carter, David P. 285Carvalho, John P. 180Casey, Mary Ellen 219,259,291,

321,350Cavanaugh, Timothy 195Chandran, Rabin 270Chang, Victoria C. 142Chapin, Kimberle C. 202Cherkes, Joseph K. 377Chiaverini, Leanne C. 81Chou, Kelvin L. 126,134,142Cogan, John Aloysius Jr. 221,322Cooper, George N. Jr. 33,36Crausman, Robert S. 353Cryan, Bruce 319Cullinen, Kathleen 113Culpepper, Larry 281

David, Sean P. 274,281DiPetrillo, Thomas A. 70Donnelly, Doreen 212Doyle, Kathleen F. 363[abs]Dubel, Gregory 213Duquette, Cathy E. 252Dworkin, Lance D. 362[abs],

364[abs]

Eaton, Charles B. 276,281Eckert, Susan 364[abs]Eisen, Jane 162Empkie, Timothy 276

Farrell, David 187Fausto-Sterling, Anne 316Feller, Alexander A. 248Feller, Edward R. 236,248Fine, Michael D. 285,287Forbes, Elizabeth A. 97Frank, Barbara 187Frazzano, Arthur 266,307Friedman, Joseph H. 4,52,88,124,

156,192,228,264,206,328,360,388

Friehs, Gerhard M. 134,137Fulton, John P. 81,146,217,288

Gardner, David 362[abs]George, Paul F. 272Ghazal, Marie 212Gilchrist, James 83Gilbert, Thomas T. 276Glicksman, Arvin S. 54,74,149Goldman, Roberta E. 281Gong, Rujun 362[abs], 364[abs]Goula, Walter J. 363[abs], 364[abs]Grace, Janet 130Greenberg, Benjamin D. 134,137, 162Gruppuso, Phiip A. 298,299

Hall-Walker, Carol 186Ham, Michael W. 362 [abs]Hebert, Megan R. 198Helfand, Stephen I. 314Hershkowitz, Melvin 239,368Heru, Alison M. 178Hesser, Jana 257Hohenhaus, Mary 79Hopkins, Richard A. 6,11Horowitz, Andrew I. 370Huschle Patricia E. 221,322, 354Jacobson, Sandra 364[abs]Johnston, L. McTyeire 330,390Julme, Thalia 347

Kacmar, Jennifer E. 230Kao, Roy L. 363[abs]Kaufman, Seth A. 70Kogut, Stephen 252Kolankiewicz, Luiz M. 363[abs]Koller, Christopher F. 411

Lambert, Lisa 364[abs]Lavallee, Laura K. 281Leddy, Tricia 391Leggatt, Nancy G. 285Lepore, Timothy J. 248Lilly, R. Eric 29Liscord, Emory E. 287Long, Rick 274Low, Greg 252Lundquist, Carla 186

Maddock, Philip G. 76Maier, Deeborth 241Mancebo, Maria 162Mansfield, Bernadette 212Marable, Sharon 39Marshall, Robert 417Maslow, Andrew 20Mayer, Kenneth 194McCarthy, Helen 186McGarry, Kelly A. 198McLaughlin, Marguerite 150,187McQuiston, Leslie D. 365Mellion, Michelle 83Midkiff, Brian D. 109Monroe, Alicia D. 274,276,304Morvarid, Babak 127Murphy, Brian L. 109

Nolan, Patricia 332Nothnagle, Melissa 230,270

O’Bell, John W. 363[abs]Okajangas, Catherine 134Oldenburg, Nicklas B.E. 59Owens, Judith 90,91Ong, Thun-How 104

Palm, Kathleen M. 169Passero, Michael A. 363[abs]Patry, Gail 150]Pezzullo, John A. 419Phillips, Katharine A. 175Pinto, Anthony 162Powers, Donya A. 84 [letter]Price, Lawrence H. 137,180

Quesenberry, Peter J. 363[abs]

Rainey, Samara E. 232Rasmussen, Steven 137,162Raynor, Hollie 241Recupero, Patricia R. 159,232Regine, Mark 252Reinert, Steven E. 365,370Retsinas, Joan 46,86,118,154, 190,

226,262, 294, 326,358,386,422

Rich, Josiah 194,212Risica, Patricia Markham 257Rochefort, David W. 407Rodriguez, Pablo 344Roy, Dennis 397

Salloway, Stephen 166Sanchez-Guijo, Fermin 363[abs]Sarni, Robert P. 285Selo, Daniel 255Shafman, Timothy D. 55Shah, Hardeek H. 381Shalvoy, Robert M. 236Shaw, Jane 274Silvia, Joanne M. 272Simmons, Emma M. 281Simon, Peter R. 347Smith, Stephen R. 276Smolski, Lisa 339Strong, David R. 169Stumpff, Jeffrey 230

Taylor, Julie Scott 230,276Teeple, Erin 236Tolentino, Karine 417Trachtenberg, Robert M. 307Triedman, Scott A. 63Turini, George A. III 365Tyrka, Audrey R. 137,180

Vares, Laura 312Viner-Brown, Samara I. 215,257,379Viticonte, Janice 299

Wall, Barry W. 205Wang, Feng 362[abs]Warren, Sharon 100Wazer, David W. 70Westlake, Robert J. 159Williams, Jane 312Williams, Karen A. 110,183,415Wilkinson, Joanne 284Wolfson, Ivan S. 114[letter],336Wood, Todd 364[abs]

TITLESA chestful of words [PL] 189A craving for sugar hastens

slavery in the West 265A plethora of quantitative

prefixes [PL] 43A perspective on gay men’s

health 195A tribute to John

Cunningham, MD 266 A vocabulary of labor [PL] 384Accelerated partial breast

irradiation: Current modalitiesand investigations 70

Advanced cardiac anesthesiaimaging techniques 20

Advances in Pharmacology[AP] 252

April’s Fool’s commentary:In praise of placebos 124

Astasia-Abasia as an incidental finding 360Atrial fibrillation [Image]Atrial fibrillation from a surgical perspective33

2006 Index�

Bat out of Hell 89Bathhouses of Manhattan 125Beating heart surgery 29Becoming a doctor 284Behavioral and massage treatments

for infant sleep problems 97Biomarkers in the human stress system:

Do they signal risk for depression? 180Breastfeeding practices of

resident physicians in RI 230Brown Medical School class

of 2006 2006Brown Medical School family

medicine at thirty: Residents’views of now and then 272

Building a successful research enterprisein family medicine: The Brownexperience 281

Cardiac outcomes assessmentand quality management 11

Caring for your lesbian patients 198Case for consistent assignment of

nurses aides in nursing homes [QP] 187Case of hypertrophic nerve roots [Image] 83Cerebrovascular disease in RI:

Rises and burden [HBN] 146Chemical imbalance or moral weakness?

Personal responsibility in a time ofbrain science 88

Childhood obesity epidemic: Key eatingand activity behaviors to address intreatment 241

Cigarette smokers who have difficultiesquitting: The role of negative mooddisturbances 169

Circumcision: A study of current parentaldecision-making 365

CME Registration, Questions, Evaluation[Pediatric sleep disorders] 107

Colorectal algorithm guidelinesfor screening [PHB] 149

Colonic intussusception in anadult [Image] 419

Combination chemotherapy and radiationtherapy for upper aerodigestive tractcancers 55

Computerized physician orderentry at hospitals in RI:A state-wide survey [AP] 252

Controlling cancer of the cervixuteri in RI [PHB] 217

Culture gaps 52

Deep brain stimulation surgery forParkinson’s Disease: The role ofneuropsychological assessment 130

Diffuse membranoproliferativeglomerulonephritis presenting aspulmonary renal syndrome [abs] 363

Doctor’s revenge 296Doctoring: Clinical skills

teaching in the 21st century 304Dreams in Neurological

Diseases 388Drug screening: Adjunct to the differential

diagnosis of drug intoxication 377

Education to improve interdisciplinarypractice of health care professionals:A pilot project 312

Epigenetic changes in bone marrow cellsco-cultured with radiation-injuredlung [abs] 363

Errata 112Evaluation of the cardiac surgery patient by

MRI and CT Imaging:The state of the art 14

Evidence of increased prostatecancer screening in RI 288

Eyes have it [PL] 356


Family medicine in words [PL] 85Family medicine residency education:

Staying on the cutting edge 270Fellowship training in family medicine at

Brown: Adding depth to breadth 274From asylum to neurobiology and

behavioral genetics: Butler Hospitaltoday 159

Gregori Rasputin, AIDS, andVictoria’s secret 329

Hazards of unrestrainedcuriosity 361

Hazards to patients in ateaching hospital 368

Health by Numbers [HBN] 41,81,110,146,183,215,257,288,

319, 347,379,415Health IT E-Newsletter [QP] 219,259Health Insurance Update [HIU] 221,322,354Health of RI’s hospitals [HBN] 319History of the predoctoral division in

the Department of Family Medicineat Brown Medical School 276

Health outcomes and health insurance:A review of recent evidence 332

Hepatocyte growth factor is a potentanti-inflammatory cytokine targetinginflamed endothelial cells [abs] 364

Homelessness and health 336Hospital Case Files: Case of

methemoglobinemia 79Hospital Case Files: Miriam Hospital

Morbidity Conference: UlcerativeColitis 255

Hospitalizations for behavioralillness in RI [HBN] 183

Humble fly: What a model systemcan reveal about the human biologyof aging 314

Ideal physician executive 232Image in Medicine 40,83,109,

213,353,419Improving health care access for

uninsured Rhode Islanders 287Improving nursing home care

[QP] 150Improving the diagnosis and

treatment of Alzheimer’sdisease 166

Improving the poor outcomes of today’shealth care 390

Index, 2005 44Inequity or iniquity? Social injustice and

medical care 328Infected teeth and blind eyes 156Intensity modulated radiation therapy 76Intimidation 192Intrapepatic calculi [image] 109Introduction: Neurostimulation 126Introduction: Radiation oncology for

the 21st century – The best is yetto be 54

Introduction to the office of the healthinsurance commissioner [HIU] 221

Introduction: Topics in sleepmedicine 90

Is health reform in Massachusettsa model for Rhode Island? 407

Judicial Diagnosis [JD] 223,381

Learning from poor outcomesI today’s health care 330

Left ventricular remodeling or restorationfor congestive heart failure 36

Letters to the editor 84,114LPS injection ameliorates renal

inflammation and injury viaNF-Kappa beta inhibition [abs] 362

May sheep safely graze? 157Medical education at Brown

Medical School 298

Medicare prescription drug plans: Theimpact on physician practice [PHB] 39

Molecular tests for detection of thesexually-transmitted pathogensNeisseria Gonorrhoeae andChlamydia trachomatis 202

Multi-cultural approach at thefoundation of medical practice 344

Mumps, branks and other impediments 297Must my doctor tell my partner?

Rethinking confidentiality in the HIVera [JD] 223

My black bag 4

Nantucket native Americansickness of 1763-4 248

Neurostimluation for epilepsy 127New age of cardiac surgery driven by tissue

engineering and biotechnology 6New prompt payment regulation

offers greater protections tophysicians 322

Obesity and overweight amongadults in RI [HBN] 257

Obsessive-compulsive disorder:Recognition across medical settings,and treatments from behaviortherapy to neurosurgery 162

Obstructive sleep apnea syndrome:Clinical features in children vs.adults 104

Olive oil in the treatment ofhypercholesterolemia [PHB] 113

Opportunities for improved quality andaccess in the office setting 400

Overtraining in young athletes 236

Perils and virtues of medicalprivacy 53

Physician’s Lexicon [PL] 43,85,115,153,189,225,261,

292,324,356,384,420Preoperative treatment of rectal

cancer 63Profiling and genetic destiny 389Promoting specialty care for

Lyme Disease [PHB] 186Psychotherapy of sexual minorities 205Public Health Briefs [PHB] 39,84,

113,149,186,217,417

Quality Partners of RI [QP] 150,187,219,259,

291,321,350

Radiation management of prostate cancer 74Recurrent clozapine induced cardiac

tamponade [abs] 364Refugee health in RI [HBN] 347Requirements for licensure of

physicians in RI [PHB] 84Retirement choices 239Reworking the patient safety equation

with liability, culture and heathcourts [JD] 381

Rhode Island Academy of FamilyPhysicians then and now 285

Rhode Island Free Clinic: Access to healthcare for the uninsured 339

Rhode Island Health IT:Project update 291,

321,350

Rhode Island institutes a newstatewide uniform physicianapplication process [HIU] 354

Rhode Island Medical JournalHeritage 46,86,118,154,

190,226,262,294,326,358,386,422

Rhode Island public health trainingprogram: Market survey findings[PHB] 417

Right of the state to sterilize 193RIte Care: Rhode Island’s success in

improving the health of childrenand families 391

Role of palliative radiation in themanagement of brain, spinal cord,and bone metastases 59

Role of Yf1 in regulating humanBNP gene expression incardiac myocytes [abs] 362

Science and technology studies: Itsrelevance to medical education andthe practice of medicine 316

Serving the spectrum of needs incommunity health centers 397

Sex, culture and health:Whatdoctors need to know 194

Sharing bad news 228Skeletal etymology, part I [PL] 115Skeletal etymology, part II [PL] 153Skin-Deep in Words [PL] 292Sleep and ADHD: A review 91Sleep in children with

developmental disabilities 94Sleep in medically compromised

children 100Smoking among pregnant WIC

participants in RI [HBN] 379So what the heck is an AHEC and what

does it mean for Brown? 307Specialized STD care in RI 212Stage at diagnosis and first course of

treatment for prostate cancer in RI,1990-2003 [HBN] 81

Successful exclusion of abdominalaortic aneurysm using anendograft [image] 213

Surgical aspects of deep brain stimulation 134

Teaching testicular self-examination inthe pediatric outpatient setting: Asurvey of pediatricians and familydoctors 370

Temper my spirits, Oh Lord 229Tertiary cardiac care services

in RI [HBN] 41Thanks for the bad news 264There’s nothing like a redhead! 5Thirty years of academic family medicine

in RI: Looking back, looking forward 267Those visceral words [PL] 225Traumatic pneumatocele [Image] 353Trends and patterns in cesarean

section rates in RI [HBN] 215

Columns KeyAP Advances in PharmacologyHBN Health by NumbersHIU Health Insurance UpdateImage Image in MedicineJD Judicial DiagnosisPHB Public Health BriefingPL Physician’s LexiconQP Quality Partners

Utilization of Connecticut andMassachusetts hospital by RIresidents, 1997-2003 [HBN] 110

Understanding families: Fromcriticalness to resilience 178

Utilization of hospital emergencydepartments, Rhode Island 2005[HBN] 415

Vagus nerve stimulation and deep brainstimulation for treatment resistantdepression 137

Vital Statistics 46,85,118,153,189,225,261,292,324,356,384,420

Vocabulary of disaster [PL] 420

What physicians need to know aboutbody dysmorphic disorder 175

What would it take? 411Words of dermatology [PL] 324Words of hematology [PL] 261

(800) 652-1051 ● www.norcalmutual.com

Whatever it is that sustains you through the daily challengesof your profession, know that you have an ally in NORCAL.

integrity

whatdrivesyou?

Call RIMS Insurance Brokerage Corporation at (401) 272-1050 to purchase NORCAL coverage.

Documents

Biohybrid Limbs - RIMS