policy - ct 7

Perspective

Improving health-care delivery in low-resource settings with nanotechnology: Challenges in multiple dimensions

James J Abbas 1 , Barbara Smith

1 , Mladen Poluta

2 ,

and Adriana Velazquez-Berumen 3

Abstract In the two decades after 1990, the rates of child and maternal mortality dropped by over 40% and 47%, respectively. Despite these improvements, which are in part due to increased access to medical technologies, profound health dis- parities exist. In 2015, a child born in a developing region is nearly eight times as likely to die before the age of 5 than one born in a developed region and developing regions accounted for nearly 99% of the maternal deaths. Recent developments in nanotechnology, however, have great potential to ameliorate these and other health disparities by providing new cost- effective solutions for diagnosis or treatment of a variety of medical conditions. Affordability is only one of the several challenges that will need to be met to translate new ideas into a medical product that addresses a global health need. This article aims to describe some of the other challenges that will be faced by nanotechnologists who seek to make an impact in low-resource settings across the globe.

Keywords Nanotechnology, global health, low-resource settings, technology transfer, commercialization, partnerships, medical device design, task shifting

Date received: 19 August 2016; accepted: 7 February 2017

Introduction

Recent analysis of data derived from the Global Burden of

Disease Report 1–13

indicated that globally, life expectancy

increased by more than 11 years during the period from

1970 to 2010. 14

This improvement was largely driven by

profound reductions in child mortality (>60%) and adult female mortality (>40%), with lower reductions in adult male mortality that varied widely by age group (15%– 35%).14,15 Throughout this 40-year period, however, the life expectancy of a person born in one of the world’s

poorer countries was consistently more than 30 years

shorter than that of a person born in one of the wealthiest. 14

In much of the world, the burden of preventable and trea-

table diseases is still staggering and poses formidable chal-

lenges for health-care systems. In 2015, nearly six million

children under the age of 5 died 16

due to preventable and

treatable diseases such as diarrhea (nearly 600,000 in 2013)

or malaria (over 450,000 in 2013). 16

In 2015, more than

800 women died each day due to complications in child-

birth. 5

Notably, the contribution of noncommunicable dis-

eases, such as heart disease and diabetes, to the global

burden of disease rose from 43% to 54% between 1990 and

1 School of Biological and Health Systems Engineering, Arizona State

University, Tempe, AZ, USA 2 Western Cape Department of Health, Cape Town, South Africa 3 Essential Medicines and Health Products Department, Health Systems

and Innovation Cluster, World Health Organization, Geneva,

Switzerland

Corresponding author:

James J Abbas, School of Biological and Health Systems Engineering,

Engineering Center G Wing, Arizona State University, Suite 346,

Tempe, AZ 85287, USA.

Email: [email protected]

Nanobiomedicine Volume 4: 1–14

ª The Author(s) 2017 Reprints and permissions:

sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1849543517701158

journals.sagepub.com/home/nab

Creative Commons CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-Non

Commercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction

and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages

(https://us.sagepub.com/en-us/nam/open-access-at-sage).

2010. 17

Collectively, these data indicate that there remains

a great need for improvements in healthcare. There exists

an urgent and persistent need to improve maternal and child

health, along with an evolving landscape with a growing

worldwide need to prevent, diagnose, monitor, and treat

noncommunicable diseases. 18,19

Perhaps most importantly,

these data point to persistence in health disparities, with a

disproportionate burden of disease on the poorest individ-

uals in the world’s poorest countries. 20–24

Finally, there is a

growing concern that over the next few decades climate

change will strongly affect population health, with the

greatest impact being that of infectious diseases on people

with few resources to prevent, diagnose, or treat such

diseases. 25,26

Hence, in this era, there are four defining features of the

global health landscape: (i) a lingering need to treat and

eradicate infectious diseases, (ii) a growing need to address

health issues related to noncommunicable diseases, 19,27,28

(iii) the persistence of profound health disparities, 20,22–24

and (iv) the ongoing effects of climate change. 25,26

The

success of the ongoing and emerging efforts to improve

global health will depend strongly on the ability of medical

technology developers to innovate new and affordable

products and deliver them to the marketplace.

A number of emerging technologies hold great potential

to address these global health needs. In particular, the con-

vergence of developments in nanotechnology, mobile tech-

nology, and information technology is enabling

development of (i) affordable laboratory or point-of-care

diagnostics, 9,10,12,29–41

(ii) remote clinic, home-based ther-

apeutics, or technology for prevention, 31,42–46

(iii)

improved communication with patients and across health-

care facilities, 47–49

and (iv) technology for broad-based

health surveillance. 50,51

These approaches, some of which

are highlighted in this special issue, 52,53

may be able to

effectively leverage cost reductions driven by consumer

technologies. While these emerging technologies hold

great promise, efforts to commercialize and successfully

deploy new medical technology are certain to face a num-

ber of challenges, especially in the areas of greatest need.

This article describes the types of challenges that might

be faced in the development and deployment of nanotech-

nology to improve health care in low-resource settings.

These include a set of challenges that would be faced in

any health-care technology venture and others that may be

unique to deployment in low-resource settings. In addition,

we provide a sampling of innovative strategies and

approaches that could support nanotechnology ventures.

In medical nanotechnology, as in other fields, the greatest

opportunities lie in the areas of greatest need. The broad

array of emerging nanotechnologies and their potential for

addressing clinical issues in global health have been

described in other recent reviews. 37,44–46,54–62

This review

aims to motivate nanotechnologists to seek out opportuni-

ties in the areas of greatest need and to enable them to

identify and directly address the challenges faced in

translating lab-based success into clinical impact in low-

resource settings.

Challenges

Emerging technologies offer an array of opportunities to

address critical issues in global health, but a variety of

challenges may be faced in the pursuit of successful

deployment of a new medical product. Technical chal-

lenges must be overcome to generate new knowledge

and/or produce new technology; market-related challenges

must be addressed to appropriately target the product for

the market conditions; human resource–related challenges

must be overcome to match human resource demands with

capacity; and finally, a range of logistical challenges must

be met to manufacture and deliver the product. Each of

these four categories of challenges is described in the fol-

lowing sections. Embedded within each of these four cate-

gories are specific infrastructure-related challenges that

arise due to the lack of high-quality infrastructure for busi-

ness and medical care delivery in low-resource settings.

Technical challenges

Recent advancements in technology have enabled

improved device versatility and functionality in a wide

variety of scenarios. This is mainly the result of advanced

material properties, miniaturization, and overall robust-

ness of the end products. However promising, many

devices fail to meet the challenges imposed by extreme

environmental conditions or shortcomings in the health-

care infrastructure.

In many low-resource settings, the physical environment

can present extreme demands on the ability of technology

to function properly. Most notably, the technology must be

able to function in the presence of humidity, temperature,

and/or dust. 32,63

The climatic conditions in some low-

resource settings may reach temperature and/or humidity

levels outside the range of typical technical specifications.

For example, the temperatures in Mali or Pakistan can

reach as high as 45�C; in Mongolia or northern Alaska as low as �30�C; and the humidity in the rain forest of Brazil, the Democratic Republic of the Congo, or Papua New Gui-

nea can be consistently above 80%. During the summer of 2015, the combination of high temperature and humidity

put the heat index at 74�C in parts of Iraq, where air- conditioning is not widely used and electricity and refrig-

eration are unreliable. One study that monitored conditions

along the supply chain in four different countries found that

samples of rapid diagnostic tests were regularly exposed to

temperatures and humidity levels that far exceeded general

guidelines for pharmaceuticals. However, due to fact that

the specific tests were designed to withstand high heat and

humidity, they were only rarely exposed to conditions that

exceeded the manufacturers’ guidelines. 64

Such studies

underscore the importance of designing technology with

2 Nanobiomedicine

the ability to withstand conditions that might be experi-

enced in such settings. In the desert and in the tropics, the

high levels of moisture, dust, and/or other contaminants

can push the limits of the core principles that underlie the

operation of a certain class of technologies or may place

additional demands on the engineering design of a spe-

cific device.

In addition to the extremes of climatic conditions, the

medical product may also have to survive and function

properly in conditions that are not well controlled. On-

site and in-transit refrigeration or humidity control may

be nonexistent or at best, unreliable. 9,32

The levels of dust

or contaminants in the clinic, clinical laboratory facility, or

at home may be similar to those experienced in the external

environment. In a recent visit to a newly constructed hospital

in a capital city in sub-Saharan Africa, it was disturbing to

note that the only ventilation in the clinical laboratory facil-

ities was provided through open windows, which invited the

dust and grime of a rapidly developing metropolis. The

designers of the imported benchtop technology to analyze

blood or urine samples may not have envisioned their device

operating under such conditions, but the validity of the mea-

surements and ultimately patient safety depend on the ability

of the technology to function properly in the presence of a

substantial amount of airborne pollutants.

A number of recent technological advancements have

been implemented to address or sidestep known challenges

such as refrigeration. These point-of-care tests avoid the

need for refrigeration through the use of dry reagents 9,65

and vaccine technologies, such as vaccines with improved

temperature stability and vaccine vial monitors—that use

temperature-sensitive dyes to indicate if a vaccine has been

exposed to temperatures that would render it ineffective. 66

Market-related challenges

With any medical technology, the question of “who are you

marketing to”? can be important to consider at an early stage

of technology development. The decision to purchase a med-

ical product may be made by national authorities, insurance

providers, hospitals or clinics, health-care providers, or by

individual users. 10,11,67

Although the critical factors in the

decision-making process may primarily be that of documen-

ted performance in randomized clinical trials, other factors

may also play a role, such as cost, brand recognition, brand

loyalty, personal contacts, or individual preferences.

In low-resource settings, the question of who are you

marketing to? may also be influenced by a number of other

factors. For large-scale efforts to reduce mortality due to

infectious disease, the dominant purchaser of medical prod-

ucts may be United Nations (UN) agencies (e.g. United

Nations International Children’s Emergency Fund (UNI-

CEF), United Nations Development Programme (UNDP),

United Nations Population Fund (UNFPA)); major interna-

tional not-for-profit aid agencies (e.g. Bill and Melinda

Gates Foundation, Cooperative for Assistance and Relief

Everywhere (CARE), Doctors Without Borders, Oxfam);

or governmental international aid organizations (e.g.

United States Agency for International Development

(USAID), Department for International Development

(DFID)). For many developers of medical products, a sin-

gle contract with one of these organizations can not only

provide an initial boost in sales and capital but it can often

lead to a stable influx of major contracts from other insti-

tutions or governments due to the visibility and high degree

of respect afforded to these organizations.

Acquisition of a major contract with a nationalized

health-care system will necessitate successful integration

into their procurement system. 68

This may require registra-

tion, documentation, price negotiation, and several levels

of approval through processes that can be opaque

and byzantine. 69

As with many of these challenges, a

well-informed local contact who has experience with the

processes can be a very valuable asset to the business

development team.

Some medical nanotechnologies may be directly mar-

keted to the consumer, which would place a different set of

demands on pricing and distribution strategies. Most

importantly, however, selling directly to the consumer in

low-resource settings presents a multifaceted challenge to

marketing. The lack of telecommunications infrastructure,

poor literacy rates, brand loyalty, and aversion to innova-

tion can all limit the ability to reach and penetrate new

markets.

Many technology developers are required to put forth

great efforts to protect intellectual property even when

manufacturing, production, and sales all take place within

one country. International considerations drastically

increase the cost, effort, and expertise required for patent

protection. 12,33,43,67

These concerns may be heightened in

many low-income countries that may not have well-

established patent regulations or enforcement capabilities.

In some instances, countries have formed regional organi-

zations (e.g. Africa Regional Intellectual Property Organi-

zation) to pool resources and simplify procedures for

inventors to obtain patent protection across a region. A

related concern for many producers is the growing preva-

lence of counterfeit medical products. 11,67,70

This has huge

implications for the pharmaceutical industry—both in terms

of patient safety and commercial competitiveness. Multia-

gency, multinational efforts are underway to reduce the

impact of such products, and the affected industries are essen-

tial partners in preventing such crimes. 11,67,70

Some efforts

are focused on the development of affordable and simple-to-

use technologies that can be used at the point of administra-

tion, to detect counterfeit medicines. 70,71

For medical

devices, a design that incorporates security and traceability

features to increase the difficulty for counterfeit production

may greatly facilitate anti-counterfeiting enforcement.

A final market-related challenge is that of interdepen-

dence. Many technologies address only one step in a com-

plex multistep process required for clinical success. The

Abbas et al. 3

simplest and most widespread example may be the inter-

dependence of diagnosis and treatment. The least expen-

sive and simplest technology for diagnosis would be

useless without an ability to treat and vice versa. Further-

more, the value of any diagnostic may be lost in an envi-

ronment where treatment is available, inexpensive, and has

historically been widely utilized. For example, one exten-

sive clinical trial demonstrated that an inexpensive rapid

diagnostic test for malaria could accurately produce a pos-

itive or negative test result, but the treatment was still

highly prescribed after a negative test result due to the

expectations of the patient and caution on the part of the

clinician. 72

Other studies have also documented a reluc-

tance to accept negative test results by both patients and

health-care workers. 73

While there have been successful

demonstrations of the positive impact of rapid diagnostic

tests on treatment decisions, 74

this interdependence is com-

plex and may require a comprehensive integration of new

technologies into the clinic environment.

Human resource challenges

In areas that have limited access to medical products, there

is often a scarcity of trained and credentialed medical per-

sonnel. The shortage of health-care workers is most severe

in many countries in sub-Saharan Africa, the Indian sub-

continent, and Southeast Asia. 75

For example, it has been

reported that sub-Saharan Africa has 10% of the world’s population and 25% of the world’s burden of disease, yet only has 1% of the world’s health-care workers.76 This paucity of suitably trained personnel may be the most sig-

nificant of all of the infrastructure-related challenges.

The notion of task shifting is the redistribution of tasks

from a highly trained individual (such as a physician) to

someone with less training, such as a nurse or a health-care

worker who has received specific training for limited num-

ber of tasks. 77,78

Task shifting may help to reduce health-

care costs in any setting but may have its greatest impact in

low-resource settings that have a shortage of trained health-

care workers. 9,63,75

Although there are only a handful of

randomized clinical trials that have investigated the

effects of task shifting, there is some evidence indicating

that the practice can be effective in improving health

outcomes. 79–81

For technology developers, explicitly

designing a technology that enables task shifting

may greatly increase the likelihood that it could be widely

adopted and used effectively in a variety of settings. For-

tunately, the nature of many nanotechnologies and their

application in rapid diagnostics are extremely well suited

to enable task shifting and their eventual success may be

primarily or entirely due to the fact that they can be readily

and reliably administered by health-care workers with lim-

ited training. Developers should keep in mind, however,

that specific aspects of procedures could have a profound

impact on adoption and eventual efficacy when used in the

field. For example, one study that investigated three

different rapid diagnostic test kits for cholera demonstrated

that two of the systems performed equivalently when used

by a laboratory technician or when task shifted to a com-

munity health worker, but the third system did not perform

as well in the hands of community health workers. 82

Design for ease-of-use is a core principle of engineering

design practices that is recommended for any technology in

any setting. However, ease-of-use often involves trade-offs

with versatility and the balance of the scale may be differ-

ent in low-resource settings than in a state-of-the-art health

facility. For example, in a well-staffed, well-funded state-

of-the-art facility, it might be preferable to purchase a

device that has the versatility to be used on infants as well

as adults but requires careful adjustments or to purchase a

multifunctional device that can perform a battery of diag-

nostics but requires more reagents and more careful and

sophisticated interpretation of results. In low-resource set-

tings, the need for ease-of-use might tip the scales in the

other direction where simple procedures for administration

and interpretation may be preferred.

An important aspect of design for ease-of-use is to avoid

or minimize the need for technology-specific training. Inte-

gration of new technology is more likely to be successful

when its functionality is similar to those routinely used by

health-care workers. In some cases, however, it may be

necessary to develop and deliver programs to train users

in the appropriate use of a device. Minimizing the need for

technology-specific training can greatly improve the like-

lihood of success and widespread use of a new medical

technology.

Design for ease-of-maintenance-and-repair is an impor-

tant adjunct to design for ease-of-use. Many medical tech-

nologies require the services of clinical engineers and/or

biomedical engineering technicians (BMETs) to ensure

proper use. 32,83–85

The clinical engineering team is respon-

sible for all aspects of health technology management: (i)

checking technical specifications, (ii) recommending spe-

cific products for procurement, (iii) configuring the device,

(iv) training clinical staff in its use, (v) communicating with

the manufacturer, (vi) establishing test and maintenance

protocols, (vii) scheduling its use to optimize availability,

(viii) maintaining a suitable supply of consumables, (ix)

device replacement, and (x) eventual decommission-

ing. 84,85

The BMET is responsible for performing routine

maintenance and repairs, which is often sufficient to keep

critical equipment in condition for safe and reliable opera-

tion. However, some manufacturers require that mainte-

nance and repairs be performed by a technician employed

by the manufacturer or by an independent technician who

has specific certification on that device. Violation of this

requirement could invalidate a warranty on a substantial

capital investment. Such policies are usually imposed to

ensure continued safe operation of the device but are a clear

deterrent to purchase and/or use in low-resource settings.

Since many clinics in low-resource settings have severe

shortages in suitably trained clinical engineers and BMET

4 Nanobiomedicine

staff, this produces another level of human resource chal-

lenges. Given these shortages, technology developers could

greatly facilitate the adoption and long-term successful

deployment of their products if they designed to reduce

demands on the technical staff in the clinic. This could

include a clear demonstration of compliance with published

technical specifications; simple procedures for setup, con-

figuration, use, and decommissioning; and clear and

straightforward procedures for safe maintenance and repair

(of at least the most common problems) by a locally based

BMET without device-specific training.

Of course, addressing any or all of these challenges

could introduce trade-offs with cost that might prove to

be devastating for sales. A simple injection system can

simplify the prophylactic administration of a drug to reduce

postpartum hemorrhage in a manner that enables task shift-

ing to a community health worker. 86

However, although

seemingly inexpensive (*US$1 per dose), this successful example of task shifting, design for ease-of-use, and design

for ease-of-maintenance-and-repair increased the per-dose

cost enough to severely limit adoption and use. 80

Successful deployment of many medical technologies

requires the expertise of several individuals in addition to

that of the health-care worker performing the procedure

and the clinical/biomedical engineering team. These may

include in-country sales and distribution teams, procure-

ment specialists, and experts to train customers in the use

of the technology. Assembling the cohort of people with

the requisite expertise and resources may be particularly

challenging in low-resource settings.

Logistical challenges

Perhaps the most daunting and unpredictable set of chal-

lenges can be grouped together as “logistics.” Collectively,

these factors can contribute greatly to the depth and width

of the valley of death. 11

Many of the design decisions that

are made early in the product development process can

have a profound impact on the team’s ability to success-

fully meet these logistical challenges. For this reason, it is

very advantageous—perhaps essential—for technology

developers to at least consider these issues, as they traverse

the stages of technical development. 33

When planning for

deployment in low-resource settings, each of these chal-

lenges can be amplified by limitations in the business infra-

structure—especially in the health-care sector.

The first of these challenges is that of field testing, 33,87

or testing in the target environment. These initial trials can

profoundly impact the product development process and

can provide powerful data to help justify the substantial

investments that will be required to bring a product to the

market. An effective plan for field testing might include

several rounds of tests to evaluate initial prototypes, con-

firm product relevance in terms of environmental and cul-

tural acceptance, evaluate the level of difficulty for product

application compliance by individuals with little or no

training, validate performance of the final design, and to

demonstrate efficacy in the target environment. 33

Even

when initial field tests have shown positive results, lack

of field testing to establish operational guidelines could

substantially slow the adoption of new technology, as has

been the case with a diagnostic test for human papilloma-

virus. 80

Execution of a field trial may require approval of

an institutional review board and/or approval by local gov-

ernmental agencies. Planning and performance of the field

trial is likely to be greatly facilitated by a strong partnership

with local clinical contacts, government agencies, and pos-

sibly international organizations that are active in the area.

For most medical technologies, the process of obtaining

regulatory approval for sale and marketing can pose sub-

stantial, time-consuming, and expensive challenges. 40

The

need for, or the type of, approval that will be required will

depend on the technology, its purpose and use, and the

country in which it will be deployed. 67,88

The processes for

obtaining the Food and Drug Administration approval for

marketing in the United States are typically time consum-

ing and resource intensive but vary greatly depending on

the nature of the device, the perceived risk, and the exis-

tence of predicate devices. For use in low-resource settings

outside of the United States, approval by the regulatory

body of the country-of-use may be required. This process

may be simplified if the device has already been approved

for marketing in the United States or in Europe. For exam-

ple, in Ethiopia, the process can be greatly streamlined if

the product is already registered and marketed by members

of the International Conference on Harmonization of Tech-

nical Requirements for Registration of Pharmaceuticals for

Human Use. 89

For many developers of nanotechnology or

other types of medical devices, the clinical need and target

markets are not restricted to a particular country or region

and therefore the process of obtaining regulatory approval

in each country of use can require a substantial investment

of time and resources. To streamline this multinational

approval process, the World Health Organization (WHO),

other international institutions, and many national regula-

tory agencies are actively promoting the harmonization of

regulations so that medical products can more rapidly and

efficiently reach the end user. 67

The logistics involved in manufacturing present a set of

challenges that are strongly influenced by policies. For

example, medical products must be manufactured in a man-

ner that complies with specific standards. 67

As with regu-

latory approval, the specific standards may depend upon

the nature of the product as well as the country-of-use.

Following the established trend with consumer products,

many medical products are now manufactured in China,

India, Brazil, and other countries. For the nanotechnologist

seeking to establish manufacturing capabilities, the most

straightforward option may be to keep manufacturing oper-

ations close to the home base of the R&D laboratory, but

this approach should be carefully considered in light of

alternative options. The primary advantages of setting up

Abbas et al. 5

manufacturing facilities close to the research labs may

include ease of transfer of technologies and techniques,

ability to perform testing early and often during the

development of manufacturing processes, familiarity with

regulations and procedures, and open communication

between technologists, manufacturers, and business man-

agers. On the other hand, the primary advantages of

setting up manufacturing facilities overseas may be a

reduction in manufacturing costs, the ability to leverage

existing manufacturing capabilities and expertise, and

proximity to some of the larger target markets.

To distribute the product to the point of care in low-

resource settings, there are some challenges that are shared

across sectors. In the World Bank index of “Ease of Doing

Business,” only two countries in sub-Saharan Africa rank

in the top quartile (South Africa and Rwanda); approxi-

mately 70% of the countries in the region rank in the lowest quartile.

69 Other challenges in these regions may be unique

to the health sector. 10

Upon arrival into the country-of-use,

import regulations and tariffs may be burdensome and

bureaucratic delays can be substantial and unpredictable. 67

Transportation from the port-of-entry to the point-of-care

may require a variety of modes of transport, each of which

may present specific demands on coordination and han-

dling. Throughout the process, security of the product from

theft, destruction, or contamination must be assured. For

health-care products, there may be additional concerns if

the product utilizes controlled substances or if there is a

potential for misuse or off-market sales. Some newly devel-

oped products may be able to tap into existing distribution

channels and procedures, especially if they are being sold

to or administered by the national health-care system or by

a major nongovernmental organization (NGO). Other prod-

ucts may require the development of new distribution chan-

nels or modifications to the procedures that are in place. In

either situation, successful distribution usually requires a

partnership with informed local contacts that have the

authority and incentive to guide the creation and mainte-

nance of distribution channels and procedures.

As mentioned earlier, for medical products that require

refrigeration, the need for storage may present very specific

logistical challenges, most of which can be directly tied to

the reliability of the electrical grid or backup systems. Other

storage requirements may not be as obvious, such as the

inherent trade-offs between access and security. For a med-

ical product to be useful, the health-care worker must have

access to the device and any consumables at the time of

need. If the product is stored in a locked cabinet that is only

accessible to a supervisor, the product may be useless when

the supervisor is off duty or in a different part of the facility.

Alternatively, storage in a location that is accessible to a

large number of employees may result in depletion of stock

due to theft. Systems that enable traceability can greatly

expand access on the front lines without comprising security.

In considering the usability of a medical device, the

most obvious considerations are those of the user at the

point-of-care. The user must have the requisite skills and

training, and procedures should be fool proof and efficient.

To maximize efficiency, it might be advantageous to con-

sider integration with concomitant procedures that are

likely to be administered. A technological solution for diag-

nosis or treatment is more likely to be used effectively if it

can be (i) administered in a single dose, minimizing the

need for patient compliance, 9,32

(ii) synchronized with an

existing checkup or treatment, (iii) useful without involv-

ing substantial preparation or planning, 9

(iv) a shared pro-

cess (such as a blood draw) with other procedures,

performed during a single visit to the clinic, 10

and (v) used

as a non- or minimally invasive procedure. Some of the less

obvious factors that could adversely affect the usability of a

medical product are the need for (i) planning (e.g. fasting

prior to a blood draw), (ii) preparation (e.g. heating or

mixing), (iii) teamwork (e.g. a procedure that requires one

person to attend to the technology while the other attends to

the patient), 10

(iv) time-sensitive procedures, 33

(v) custo-

mization (e.g. dosing or scaling based on age or body

weight), or (vi) calibration (establishing a reference to a

gold standard prior to use). Removing such obstacles in the

hectic environment of an outpatient clinic or overcrowded

hospital ward would ensure wider and more accurate use of

the medical technology.

Among clinical engineers, it is often cited that the cost

of purchasing a medical device is the “tip of the iceberg”

and represents only a small portion of the cost of owner-

ship. 90,91

The up-front capital costs are often only a small

portion of what will be spent on installation, consumables,

maintenance, repairs, and decommissioning. 83

For some

medical applications of nanotechnology, such as certain

rapid diagnostic systems, the design of the system might

completely eliminate many of these costs and the primary

cost factor would be that of consumables. For these sys-

tems, minimizing the cost of consumables minimizes the

cost of ownership; systems that require costly single-use

cartridges—especially those that must be provided by the

equipment manufacturer—may incur operational costs

that are prohibitively high. In addition, systems that use

handheld or benchtop units for measurements or adminis-

tration may require costly regular maintenance and repair

to ensure patient safety. For use in any setting, but particu-

larly in low-resource settings, it is advantageous to design a

system in a manner that minimizes the need for maintenance,

simplifies maintenance procedures, requires only standard

tools and parts to perform maintenance procedures, and has

built-in capability to verify proper execution of maintenance

procedures. In addition, the decommissioning of medical

equipment can incur substantial financial as well as environ-

ment costs. 83

Finally, the cost of operation may not only

include the price, difficulties, and uncertainties of stocking

a suitable supply of nonexpired consumables but may also

include the costs for specialized handling (such as refrigera-

tion, mixing, or secure storage) and specialized procedures

for sample disposal. 32

6 Nanobiomedicine

The final logistical challenge in this list is that of post-

market surveillance and outcomes assessment. A system

that produces good results in a research lab, in a teaching

hospital, and then in a clinical trial may fail in everyday

use. Such failures can be due to poor product performance

in the field, a failure to follow usage protocols, poor storage

practices, use of expired samples or components, or simply

failure to use the product. Thorough postmarket surveil-

lance is challenging in any environment and will be partic-

ularly challenging in low-resource settings. Systems

designed to facilitate good record keeping or mobile

phone–based data collection 36

could greatly enhance the

quality and quantity of postmarket surveillance in a manner

that will ultimately improve the efficacy of the device.

However, more data do not always add value and eHealth

or mobile phone–based solutions are themselves subject to

the same concerns about efficacy and cost-effectiveness in

real-world settings. 92

Recent reviews point to the need for

more field-testing and more outcomes data. 48,51,93,94

Addressing the multidimensional challenge

In the design of medical technology, the most obvious and

immediate design objectives are to address an important

clinical need in an affordable manner. When targeted usage

is in low-resource settings, the design and development

teams will be faced with the array of challenges outlined

above. In most instances, it would be advantageous, if not

imperative, to identify those challenges and to work with

end users to address them head-on, early in the design and

development process. 9,10

Such an undertaking would con-

stitute a multiobjective optimization problem that is riddled

with the uncertainties inherent in the technology, physiol-

ogy, international markets, regulations, procurement poli-

cies, human factors, and cross-cultural dynamics.

Achieving the optimal design may not be possible or fea-

sible, but the likelihood of substantial clinical impact can

be greatly increased by attending to the array of challenges

and designing to achieve the characteristics outlined in

Figure 1 that are specifically identified by the end user or

are highly relevant to the targeted application.

Promising trends and innovative approaches to translation

The challenges described above can be intimidating not

only because they are numerous and substantial but also

because they are interrelated. Some of these challenges

may have implications for the technical specifications and

technical design characteristics of the device; others may

have implications for the selection of a suitable business

model and/or for the composition of the business team.

Collectively, they emphasize the need for nanotechnolo-

gists to take a thoughtful and comprehensive approach to

product development and translation into low-resource

settings. In addition, these challenges highlight the further

need to recognize and plan early on in the venture in order

to facilitate efficient progress.

Although the mountain of challenges forebodes a long

and difficult climb, it is encouraging to note that there have

been many recent successes. 80,95,96

In addition, a number of

new programs have been initiated that are designed to facil-

itate the process of developing and deploying technology in

low-resource settings. These include the Stanford-India Bio-

design Program, 97

Rice 360�,98 Engineering World Health, and the IDEAS Program at Washington University School of

Medicine. 99

Some emerging technologies show great prom-

ise, especially in the space that is at the intersection of nano-

technology and information technology. 35,36,39

In addition to

the rapid advances in technology, there are also a number of

new initiatives and trends on the international development

landscape and innovative approaches to translation that

could accelerate the adoption and impact of new technolo-

gies in low-resource settings. Some of these promising

trends and innovative approaches to translation are briefly

discussed below.

•meets an important clinical need

•is low-cost

•considers local environmental and cultural factors

general characteristics

•minimal infrastructure demands (e.g. refrigeration)

•long shelf-life

•durable

•provides real-time results (diagnostics/therapy)

•provides actionable results (for diagnostics)

technical characteristics:

•inexpensive

•high-volume client base

market-related characteristics:

•simple to learn to use and simple to use

•facilitates task-shifting

•few demands along deployment chain

human resource-related characteristics:

•low regulatory hurdles

•routine manufacturing processes

•utilizes existing distribution channels

•straightforward, efficient deployment at point-of-care

•requires minimal planning or preparation

•low usage costs

•requires minimal maintenance

•facilitates post-market surveillance

logistics-related characteristics:

•meets an important clinical need

•is low-cost

•considers local environmental and cultural factorsff

gengengengengeng eraeraeraeraeralllllgengeneraerall chachachachacharacracracracracterterterterteristististististicsicsicsicsicschacharacracterterististicsics

•minimal infrastructure demands (e.g. refrigeration)

•long shelf-life

•durable

•provides real-time results (diagnostics/therapy)

•provides actionable results (for diagnostics)

ttttttteeeeeeechnchnchnchnchnicaicaicaicaicalllllchnchnicaicall chachachachacharacracracracractttttchacharacractteeeeeeeriririririririsssssssticticticticticticticsssssss:::::::

•inexpensive

•high-volume client base

marmarmarmarmarketketketketket rere-re-reremarmarketket re-relllllllateateateateateddddd ateatedd cccccccharharharharharaaaaaharharaacccccccttttttterererererereriiiiiiissssssstttttttiiiiiiicccccccsssssss:::::::

•simple to learn to use and simple to use

•facilitates task-shifting

•few demands along deployment chain

humhumhumhumhumanananananhumhumanan rrrrrrresoesoesoesoesourcurcurcurcurce re re-re-re relaelaelaelaelatedtedtedtedted chchchchcharaaraaraaraaractectectectecterisrisrisrisristictictictictics:s:s:s:s:esoesourcurce-re-relaelatedted chcharaaractecterisristictics:s:

lololololololologgggggggggiiiiiiiiststststststststiiiiiiiicscscs-cs-cs rrrrrcs-cs-cs-rrreeeeeeeellllllllatatatatatatatateeeeeeeedddddddd cccccccchhhhhhhharaaraaraaraaractctctctctaraaraaractctcteeeeeeeerrrrrrrriiiiiiiiststststststststiiiiiiiics:cs:cs:cs:cs:cs:cs:cs:

general characteristics

technical characteristics:

market-related characteristics:

human resource-related characteristics:

logistics-related characteristics:

Figure 1. Key design objectives in medical nanotechnology for low-resource settings. Although the most obvious design objec- tives are that the technology should meet an important clinical need and it should be affordable by those that would use it, there is a long list of other characteristics that are either necessary for, or would greatly increase the likelihood of, successful translation and widespread use in low-resource settings.

Abbas et al. 7

Emerging economies and expanding markets

While the array of market challenges may be daunting,

there are many indications that new markets are emerging

and that the sizes of potential markets are increasing. Eco-

nomic development around the world has drastically

increased the purchasing capacity of a number of countries

and private individuals. In the year 2000, 57 countries were

classified by the World Bank as “low income”; by 2015, 21

of those countries had transitioned to “lower-middle

income,” 4 to “upper-middle income,” and 1 to “high

income.” 100

These included several countries from South-

east Asia and sub-Saharan Africa. Such economic develop-

ment can result in improved markets for medical

technologies through increased public sector support for

national health programs and through increased purchasing

capacity in the private sector. The growth in the private

sector is primarily due to the increased demand for

health-care services by the growing middle class that will

be paid for by direct payment or through private insurance

carriers.

International initiatives

Since the turn of the century, a number of international

initiatives have been directed at improving lives by

increasing the intensity, efficacy, efficiency, and impact

of development activities. These initiatives have been

either directed or strongly supported by the United

Nations and have been the result of a coordinated effort

from a number of UN agencies, member state govern-

ments, and NGOs. For technologists interested in meeting

clinical needs in low-resource settings, such initiatives are

important because they can help to rally the international

community around specific technologies, to create or sta-

bilize markets, and to promote best practices that are tech-

nology based. Some of the most important of these

initiatives include

� Millennium Development Goals: At the UN Millen- nium Declaration in the year 2000, world leaders

adopted a number of developments targets to be

achieved worldwide by the year 2015; these are now

known as the Millennium Development Goals

(MDGs). This list included several health-related

goals: most notably reduce child mortality (MDG

4); improve maternal health (MDG 5); and combat

HIV/AIDS, malaria, and other diseases (MDG 6).

For each goal, the Declaration adopted specific

metrics and targets. This Declaration provided a

framework for the development community and

governments that has been used to promote and

coordinate efforts to reach those goals. In 2016, it

is now clear that these goals have not yet been fully

achieved, but it is also clear that substantial progress

has been made. 101

� Sustainable Development Goals: Over the past sev- eral years, the post-2015 Development Agenda has

defined a framework that will serve to continue to

guide the development community beyond the MDG

era. At the 2015 UN Summit, world leaders adopted

a new set of goals that build upon the progress over

the previous 15 years and have a strong emphasis on

sustainability; these have been termed the Sustain-

able Development Goals (SDGs). 102

� UN Commission on Life-Saving Commodities for Women and Children (UNCoLSC)

103 : In 2012, the

UNCoLSC was established to promote and galva-

nize efforts to increase access for women and chil-

dren to critical medical products. The Commission

identified 13 affordable lifesaving commodities and

developed a set of recommendations for improving

their effectiveness and accessibility.

� Interagency list of medical devices for essential interventions for reproductive, maternal, newborn,

and child health (RMNCH) 104

: Recently, a coordi-

nated effort by UNICEF, UNFPA, and WHO pro-

duced this comprehensive report, 104

which aims to

strengthen health-care systems by identifying the

medical devices required to provide the essential

RMNCH interventions defined by existing WHO

guidelines and publications. Specifically, it provides

guidance for equipping various types of medical

facilities and information describing the needs for

medical equipment at each point in the continuum

of care in RMNCH. 104

� Action Agenda from the Third International Confer- ence on Financing for Development

105 : In Addis

Ababa in the summer of 2015, world leaders met

and committed to an agenda of investment and coop-

eration to promote development. The Action

Agenda includes a number of articles that specifi-

cally address public health, public health infrastruc-

ture, health product research and development,

human resource capacity, technology, innovation,

regulations, international trade, intellectual property

protection, multisector collaborations, and enhance-

ments to the business environment. 105

For technology developers seeking to address critical

global health issues, these international initiatives and com-

mitments can help to define R&D targets, provide a frame-

work and opportunities for collaboration, and offer a strong

justification for financial support in proposals for grants or

investment.

Local production of medical products in low-resource settings

In many countries, all or the majority of health-care equip-

ment and supplies are imported and acquired with funds

from one of two primary sources: (i) the national health

8 Nanobiomedicine

programs—leading to depletion in foreign reserves and

contributing to unfavorable trade deficits or (ii) NGOs—

which provide donations through an unsustainable model.

There is a growing interest in reducing this dependence on

imported medical products by establishing and strengthen-

ing the local heath industry sector. Such initiatives to sup-

port “local production” are intended to simultaneously

improve health and promote economic development and

therefore they would address the core issues in the SDGs

in an integrated manner.

Recently, WHO has completed a set of studies to inves-

tigate the feasibility of local production of medical prod-

ucts in Sub-Saharan Africa. 95,106–108

These studies identify

a broad array of challenges—most of which are those

described in the previous section of this report. Ventures

that pursue local production are likely to find an additional

set of challenges associated with manufacturing in low-

resources settings. These often include issues related to

supply chain, workforce, regulations, taxes, and so

on. 107,108

The barriers to local production will vary across

countries and across regions, depending predominately

upon the nature of the medical product. For example, the

demands on infrastructure would be different for the pro-

duction of pharmaceuticals, consumables (e.g. gloves, syr-

inges, gowns), small medical devices (e.g. blood pressure

monitors, ultrasound probes), or larger medical devices

(e.g. X-ray machines). In addition to the infrastructure and

logistical issues, local production ventures might also con-

front obstacles to market penetration due to substantial bias

toward imported products, not only from potential end

users (such as clinicians or patients) but also from govern-

ment procurement agencies. 67,95

Despite these challenges, there is considerable interest

in promoting local production, particularly in sub-Saharan

Africa 95,105–109

because of the untapped potential for inno-

vation 110

and because the possible benefits are so high—

both in terms of increased access to medical products and in

terms of economic development. In addition, there are

examples of success in Brazil, Russia, India, and

China, 110–112

as well as in other countries such as South

Africa, 113,114

Nigeria, and Jordan. 115

For foreign technology developers, successful promo-

tion of local production could result in the creation of a

local competitor for an imported product, but only if the

local product could be used as a direct substitute for the

imported one. The most probable and substantial impacts of

efforts to develop local industry are likely to provide an

improvement in the business environment, favorable to

both domestic and foreign producers. Efforts to promote

local production could channel resources toward improve-

ments in physical and health-care infrastructure, increases

in quantity and quality of the healthcare workforce, simpli-

fication of regulatory policies and procedures, and

increased transparency in government procurement proce-

dures. 95,108

Lastly, the development of a local health tech-

nology industry will produce potential partners for foreign

technology developers. Such partnerships may prove to be

the most efficient way to accelerate and amplify the impact

of new technologies.

Innovative partnerships

Recently, a number of partnerships between governmental,

nongovernmental, academic and for-profit institutions have

been developed to address a variety of issues related to the

shortage of access to medical products and quality health-

care. 116–120

Such partnerships, some of which involve insti-

tutions from more than one country, are helping to address

the need for innovation that is highly focused on user

needs, 33,117

shortages in human resources, 117,118

the fail-

ures of distribution systems, 116

and the obstacles in doing

business described in the previous section. The collective

impact of these partnerships may help to improve the envi-

ronment for emerging medical nanotechnologies. Perhaps

more importantly, some technology developers may be

able to join into existing partnerships or use them as models

for developing new ones.

In the specific realm of medical technology, several

partnerships have been established to address the shortages

in biomedical and clinical engineers, as well as BMETs.

One program, which is supported by the Fogarty Interna-

tional Centre, is directed at “Developing Innovative Inter-

disciplinary Biomedical Engineering Programs in Africa.”

This program provides training for biomedical engineers

and other medical and business professionals through a

partnership that involves Northwestern University (USA),

the University of Cape Town (South Africa), the University

of Ibadan and Lagos University (Nigeria), the University of

Bamako (Mali), and the University of Nairobi (Kenya). To

train BMETs, Engineering World Health, a US-based not-

for-profit organization, has partnered with Duke University

(USA) and several hospitals in Rwanda, Cambodia, Hon-

duras, Ghana, and Nigeria. A unique aspect of this exten-

sive program is that it includes a for-profit company,

General Electric, which provides financial support for the

training program.

The expanding and evolving landscape of partnerships

between private foundations, international organizations,

multinational corporations, government aid agencies, and

host governments has helped to expand or produce new

markets for medical products. Several broad-based partner-

ships are directed at increasing access to medical products

by shaping the economic landscape, coordinating R&D and

business development efforts, and supporting innovation in

technology, business, and government practices. For exam-

ple, to address the barriers faced in adopting a more effec-

tive treatment of severe malaria (injectable artesunate), the

Clinton Health Access Initiative partnered with UNITAID,

the United Kingdom’s DFID, Medicines for Malaria Ven-

ture, and the governments of Nigeria, Uganda, Cameroon,

Malawi, Kenya, and Zambia. One of the partners, UNI-

TAID, is itself a multinational organization with 29

Abbas et al. 9

member countries that is supported in large part through an

air ticket levies imposed in some member countries. Med-

ical technology developers may be able to greatly acceler-

ate testing, distribution, and adoption of their products by

tapping into such broad-based networks of partners.

An important feature for most, if not all, of these

efforts is that they strive to be true partnerships. This

emphasis on bidirectional exchange and collaboration is

part of a growing trend in development activities to shift

away from direct aid and to focus on partnership and

cross-sector collaboration to achieve sustainable devel-

opment. 33,40,110,118,121–124

The growing emphasis on an

approach that values all partners as potential innovators

has perhaps never been as prominent as in the recent

2015 International Conference on Financing for

Development. 105

Concluding remarks

The success of the persistent, and hopefully accelerating,

efforts to improve global health will depend strongly on the

ability of medical technology developers not only to inno-

vate new and affordable products but also to deliver them to

the marketplace. As a developer sets off to pursue these

goals, the challenges, as outlined in this review, will be

numerous and formidable. 80

However, the confluence of a

number of factors—the growing base of science and engi-

neering knowledge to support new technological develop-

ments, the widespread availability of communication and

information technologies, 47,125–127

the expanding array of

intersector and international partnerships, 105,122

and the

emerging economies in many parts of the world—may work

to remove some of these obstacles and accelerate progress.

Technology developers may be able to increase their like-

lihood of success by identifying key trends in global health

and the global health community, by carefully characterizing

the multidimensional array of challenges specific to their

technology, and by adopting strategies for technology and

business development that maximize their ability to benefit

from ongoing trends as they work to address the complex set

of challenges on the path to clinical impact.

Readers considering deployment of nanotechnology in

global health are recommended to review specific case

studies. 33,80,112

Suggested readings are also available on

specific topics, such as global burden of disease, 13

human

resource capacity, 76

task shifting, 79

noncommunicable dis-

eases, 19,28

and infectious diseases. 54–62

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect

to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research,

authorship, and/or publication of this article.

References

1. United Nations Children’s Fund. United Nations Inter-

agency Group for Child Mortality Estimation. Levels and

Trends in Child Mortality Report 2012. New York: United

Nations Children’s Fund, 2012.

2. UN Inter-agency Group for Maternal Mortality Estimation.

Trends in maternal mortality: 1990 to 2010: WHO, UNICEF,

UNFPA and The World Bank estimates. Geneva: World

Health Organization, 2012.

3. Jamison DT, Summers LH, Alleyne G, et al. Global health

2035: a world converging within a generation. Lancet 2013;

382: 1898–1955.

4. United Nations Children’s Fund. United Nations Inter-

agency Group for Child Mortality Estimation. Levels and

Trends in Child Mortality Report 2015. New York: United

Nations Children’s Fund, 2015.

5. Maternal Mortality Estimation Inter-Agency Group. Trends

in maternal mortality: 1990 to 2015: estimates by WHO,

UNICEF, UNFPA, World Bank Group and the United

Nations Population Division. Geneva: World Health Organi-

zation, 2015.

6. Frost LJ and Reich MR. ACCESS: How do good health tech-

nologies get to poor people in poor countries? Cambridge:

Harvard Center for Population and Development Studies,

2008.

7. Simiyu K, Daer AS and Singer PA. Stagnant health technol-

ogies. Science 2010; 330: 1483–1484.

8. Labarre P. Engineering global health. IEEE Pulse 2011; 2(1):

18–25.

9. Yager P, Domingo GJ and Gerdes J. Point-of-care diagnostics

for global health. Annu Rev Biomed Eng 2008; 10: 107–144.

10. Pai NP, Vadnais C, Denkinger C, et al. Point-of-care testing

for infectious diseases: diversity, complexity, and barriers in

low- and middle-income countries. PLoS Med 2012; 9:

e1001306.

11. World Health Organization. Medical devices: managing the

mismatch: an outcome of the priority medical devices project.

Geneva: World Health Organization, 2010.

12. Derda R, Gitaka J, Klapperich CM, et al. Enabling the devel-

opment and deployment of next generation point-of-care

diagnostics. PLoS Negl Trop Dis 2015; 9: e0003676.

13. GBD 2013 Mortality and Causes of Death Collaborators.

Global, regional, and national age–sex specific all-cause and

cause-specific mortality for 240 causes of death, 1990–2013:

a systematic analysis for the Global Burden of Disease Study

2013. Lancet 2015; 385: 117–171.

14. Wang H, Dwyer-Lindgren L, Lofgren KT, et al. Age-specific

and sex-specific mortality in 187 countries, 1970–2010: a

systematic analysis for the Global Burden of Disease Study

2010. Lancet 2012; 380: 2071–2094.

15. You D, Hug L, Ejdemyr S, et al. Global, regional, and

national levels and trends in under-5 mortality between

1990 and 2015, with scenario-based projections to 2030: a

systematic analysis by the UN Inter-Agency Group for Child

Mortality Estimation. Lancet 2015; 386: 2275–2286.

10 Nanobiomedicine

16. World Health Organization. Global Health Observatory data

repository. Geneva: World Health Organization, 2016.

17. Murray CJL, Vos T, Lozano R, et al. Disability-adjusted life

years (DALYs) for 291 diseases and injuries in 21 regions,

1990–2010: a systematic analysis for the Global Burden of

Disease Study 2010. Lancet 2012; 380(9859): 2197–2223.

18. Hogerzeil HV, Liberman J, Wirtz VJ, et al. Promotion of

access to essential medicines for non-communicable dis-

eases: practical implications of the UN Political Declaration.

Lancet 2013; 381: 680–689.

19. Horton R. Non-communicable diseases: 2015 to 2025. Lancet

2013; 381: 509–510.

20. Webster J, Lines J, Bruce J, et al. Which delivery systems

reach the poor? A review of equity of coverage of ever-

treated nets, never-treated nets, and immunisation to reduce

child mortality in Africa. Lancet Infec Dis 2005; 5:

709–717.

21. Engle PL, Fernald LCH, Alderman H, et al. Strategies for

reducing inequalities and improving developmental outcomes

for young children in low-income and middle-income coun-

tries. Lancet 2011; 378: 1339–1353.

22. Walker SP, Wachs TD, Grantham-McGregor S, et al.

Inequality in early childhood: risk and protective factors for

early child development. Lancet 2011; 378: 1325–1338.

23. Nachega JB, Uthman OA, Peltzer K, et al. Association

between antiretroviral therapy adherence and employment

status: systematic review and meta-analysis. Bull World

Health Organ 2015; 93: 29–41.

24. Di Cesare M, Khang Y-H, Asaria P, et al. Inequalities in non-

communicable diseases and effective responses. Lancet 2013;

381: 585–597.

25. McMichael AJ. Globalization, climate change, and human

health. N Engl J Med 2013; 368: 1335–1343.

26. Haines A, Smith KR, Anderson D, et al. Policies for accel-

erating access to clean energy, improving health, advancing

development, and mitigating climate change. Lancet 2007;

370: 1264–1281.

27. Clark H. NCDs: a challenge to sustainable human develop-

ment. Lancet 2013; 381: 510–511.

28. Alleyne G, Binagwaho A, Haines A, et al. Embedding non-

communicable diseases in the post-2015 development

agenda. Lancet 2013; 381: 566–574.

29. Yansouni CP, Bottieau E, Lutumba P, et al. Rapid diagnostic

tests for neurological infections in Central Africa. Lancet

Infec Dis 2013; 13: 546–558.

30. Lawn SD, Mwaba P, Bates M, et al. Advances in tubercu-

losis diagnostics: the Xpert MTB/RIF assay and future pros-

pects for a point-of-care test. Lancet Infec Dis 2013; 13:

349–361.

31. das Neves J, Amiji MM, Bahia MF, et al. Nanotechnology-

based systems for the treatment and prevention of HIV/AIDS.

Adv Drug Deliv Rev 2010; 62: 458–477.

32. Weigl B, Boyle D, de los Santos T, et al. Simplicity of use: a

critical feature for widespread adoption of diagnostic tech-

nologies in low-resource settings. Expert Rev Med Devices

2009; 6: 461–464.

33. Kumar AA, Hennek JW, Smith BS, et al. From the bench to

the field in low-cost diagnostics: two case studies. Angew

Chem Int Ed Engl 2015; 54: 5836–5853.

34. Martinez AW, Phillips ST, Butte MJ, et al. Patterned paper as

a platform for inexpensive, low-volume, portable bioassays.

Angew Chem Int Ed Engl 2007; 46: 1318–1320.

35. Ozcan A. Mobile phones democratize and cultivate next-

generation imaging, diagnostics and measurement tools. Lab

Chip 2014; 14: 3187–3194.

36. Nemiroski A, Christodouleas DC, Hennek JW, et al. Univer-

sal mobile electrochemical detector designed for use in

resource-limited applications. Proc Natl Acad Sci U S A.

2014; 111: 11984–11989.

37. Tallury P, Malhotra A, Byrne LM, et al. Nanobioimaging and

sensing of infectious diseases. Adv Drug Deliv Rev 2010; 62:

424–437.

38. van Heerden A, Tomlinson M and Swartz L. Point of care in

your pocket: a research agenda for the field of m-health. Bull

World Health Organ 2012; 90: 393–394.

39. Whitesides G. The lab finally comes to the chip! Lab Chip

2014; 14: 3125–3126.

40. Caliendo AM, Gilbert DN, Ginocchio CC, et al. Better tests,

better care: improved diagnostics for infectious diseases. Clin

Infect Dis 2013; 57(suppl 3): S139–S170.

41. Laksanasopin T, Guo T, Nayak S, et al. A smartphone dongle

for diagnosis of infectious diseases at the point of care. Sci

Tran Med 2015; 7: 1–9.

42. Shet A and de Costa A. India calling: harnessing the promise

of mobile phones for HIV healthcare. Trop Med Int Health.

2011; 16: 214–216.

43. du Toit LC, Pillay V and Choonara YE. Nano-microbicides:

challenges in drug delivery, patient ethics and intellectual

property in the war against HIV/AIDS. Adv Drug Deliv Rev

2010; 62: 532–546.

44. Sharma P and Garg S. Pure drug and polymer based nano-

technologies for the improved solubility, stability, bioavail-

ability and targeting of anti-HIV drugs. Adv Drug Deliv Rev

2010; 62: 491–502.

45. Santos-Magalhaes NS and Mosqueira VC. Nanotechnology

applied to the treatment of malaria. Adv Drug Deliv Rev 2010;

62: 560–575.

46. Romero EL and Morilla MJ. Nanotechnological approaches

against Chagas disease. Adv Drug Deliv Rev 2010; 62:

576–588.

47. Seidenberg P, Nicholson S, Schaefer M, et al. Early infant

diagnosis of HIV infection in Zambia through mobile phone

texting of blood test results. Bull World Health Organ 2012;

90: 348–356.

48. Free C, Phillips G, Galli L, et al. The effectiveness of mobile-

health technology-based health behaviour change or disease

management interventions for health care consumers: a sys-

tematic review. PLoS Med 2013; 10: e1001362.

49. Thirumurthy H and Lester RT. M-health for health beha-

viour change in resource-limited settings: applications to

HIV care and beyond. Bull World Health Organ 2012; 90:

390–392.

Abbas et al. 11

50. Rajatonirina S, Heraud JM, Randrianasolo L, et al. Short

message service sentinel surveillance of influenza-like illness

in Madagascar, 2008–2012. Bull World Health Organ 2012;

90: 385–389.

51. World Health Organization. mHealth – new horizons for

health through mobile technologies. Geneva: World Health

Organization, 2011.

52. Miller E and Sikes HD. Addressing barriers to the develop-

ment and adoption of rapid diagnostic tests in global health.

Nanobiomedicine 2015; 2: 6.

53. Myers NM, Strydom EE, Sweet J, et al. saltPAD: a new

analytical tool for monitoring salt iodization in low resource

settings. Nanobiomedicine 2016; 1: 1–9.

54. Abou Neel EA, Bozec L, Perez RA, et al. Nanotechnology in

dentistry: prevention, diagnosis, and therapy. Int J Nanomed

2015; 10: 6371–6394.

55. Antiochia R, Bollella P, Favero G, et al. Nanotechnology-

based surface plasmon resonance affinity biosensors for in

vitro diagnostics. Int J Anal Chem 2016; 2016: 2981931.

56. Bobo D, Robinson KJ, Islam J, et al. Nanoparticle-based

medicines: a review of FDA-approved materials and clinical

trials to date. Pharm Res 2016; 33: 2373–2387.

57. Cheon SA, Cho HH, Kim J, et al. Recent tuberculosis diag-

nosis toward the end TB strategy. J Microbiol Methods 2016;

123: 51–61.

58. Lifson MA, Ozen MO, Inci F, et al. Advances in biosensing

strategies for HIV-1 detection, diagnosis, and therapeutic

monitoring. Adv Drug Deliv Rev 2016; 103: 90–104.

59. Liu Y and Chen C. Role of nanotechnology in HIV/AIDS

vaccine development. Adv Drug Deliv Rev 2016; 103: 76–89.

60. Syedmoradi L, Daneshpour M, Alvandipour M, et al. Point of

care testing: the impact of nanotechnology. Biosens Bioelec-

tron 2017; 87: 373–387.

61. Torres-Sangiao E, Holban AM, and Gestal MC. Advanced

nanobiomaterials: vaccines, diagnosis and treatment of infec-

tious diseases. Molecules 2016; 21: E867.

62. Wen AM and Steinmetz NF. Design of virus-based nanoma-

terials for medicine, biotechnology, and energy. Chem Soc

Rev 2016; 45: 4074–4126.

63. Andronikou S, McHugh K, Abdurahman N, et al. Paediatric

radiology seen from Africa. Part I: providing diagnostic ima-

ging to a young population. Pediatr Radiol 2011; 41:

811–825.

64. Albertini A, Lee E, Coulibaly SO, et al. Malaria rapid

diagnostic test transport and storage conditions in Burkina

Faso, Senegal, Ethiopia and the Philippines. Malar J 2012;

11: 406.

65. Stevens DY, Petri CR, Osborn JL, et al. Enabling a micro-

fluidic immunoassay for the developing world by integration

of on-card dry reagent storage. Lab Chip 2008; 8: 2038–2045.

66. Kartoglu U and Milstien J. Tools and approaches to ensure

quality of vaccines throughout the cold chain. Expert Rev

Vaccines 2014; 13: 843–854.

67. World Health Organization, World Intellectual Property

Organization and World Trade Organization. Promoting

access to medical technologies and innovation: Intersections

between public health, intellectual property and trade. Gen-

eva: World Health Organization, World Intellectual Property

Organization, World Trade Organization, 2012.

68. Procurement Process Resource Guide. WHO medical device

technical series. Geneva: World Health Organization, 2011.

69. Doing Business 2015. Going beyond efficiency. Washington,

DC: The World Bank, 2014.

70. Kumar B and Baldi A. The challenge of counterfeit drugs: a

comprehensive review on prevalence, detection and preven-

tive measures. Curr Drug Saf 2016; 11(2): 112–120.

71. Weaver AA and Lieberman M. Paper test cards for presump-

tive testing of very low quality antimalarial medications. Am

J Trop Med Hyg 2015; 92: 17–23.

72. Lubell Y, Reyburn H, Mbakilwa H, et al. The impact of

response to the results of diagnostic tests for malaria: cost-

benefit analysis. BMJ 2008; 336: 202–205.

73. Diggle E, Asgary R, Gore-Langton G, et al. Perceptions of

malaria and acceptance of rapid diagnostic tests and related

treatment practises. Malar J 2014; 13: 502.

74. Kyabayinze D, Asiimwe C, Nakanjako D, et al. Use of RDTs

to improve malaria diagnosis and fever case management at

primary health care facilities in Uganda. Malar J 2010; 9:

200.

75. Sidibe M and Campbell J. Reversing a global health work-

force crisis. Bull World Health Organ 2015; 93: 3.

76. Crisp N. Global health capacity and workforce development:

turning the world upside down. Infect Dis Clin North Am

2011; 25: 359–367.

77. World Medical Association. WMA resolution on task shifting

from the medical profession. New Delhi: World Medical

Association, 2009.

78. Engelman D, Kado JH, Reményi B, et al. Focused cardiac

ultrasound screening for rheumatic heart disease by briefly

trained health workers: a study of diagnostic accuracy. Lancet

Glob Health 2016; 4: e386–e394.

79. Joshi R, Alim M, Kengne AP, et al. Task shifting for non-

communicable disease management in low and middle

income countries – a systematic review. PLoS One 2014; 9:

e103754.

80. Matthias DM, Taylor CH, Sen D, et al. Local markets for

global health technologies: lessons learned from advancing

6 new products. Glob Health Sci Pract 2014; 2(2): 152–164.

81. Ogedegbe G, Gyamfi J, Plange-Rhule J, et al. Task shifting

interventions for cardiovascular risk reduction in low-income

and middle-income countries: a systematic review of rando-

mised controlled trials. BMJ Open 2014; 4: e005983.

82. Kalluri P, Naheed A, Rahman S, et al. Evaluation of three

rapid diagnostic tests for cholera: does the skill level of the

technician matter? Trop Med Int Health 2006; 11(1): 49–55.

83. Malkin RA. Design of health care technologies for the devel-

oping world. Annu Rev Biomed Eng. 2007; 9: 567–587.

84. World Health Organization. Medical equipment maintenance

programme overview. Geneva: World Health Organization,

2011.

85. Wang B. Medical equipment maintenance: management and

oversight. London: Morgan & Claypool, 2012.

12 Nanobiomedicine

86. Stanton CK, Newton S, Mullany LC, et al. Effect on post-

partum hemorrhage of prophylactic oxytocin (10 IU) by

injection by community health officers in Ghana: a

community-based, cluster-randomized trial. PLoS Med

2013; 10: e1001524.

87. Kumar AA, Chunda-Liyoka C, Hennek JW, et al. Evalua-

tion of a density-based rapid diagnostic test for sickle cell

disease in a clinical setting in Zambia. PLoS One 2014; 9:

e114540.

88. The Law Library of Congress Global Legal Research Cen-

ter. Approval of medical devices. Washington: The Law

Library of Congress Global Legal Research Center, 2014.

89. Food, Medicine and Health Care Administration and Con-

trol Authority of Ethiopia (FMHACA). Guideline for regis-

tration of medicines. Addis Ababa: Food, Medicine and

Health Care Administration and Control Authority of Ethio-

pia (FMHACA), 2014.

90. World Health Organization. Medical devices: managing the

mismatch – barriers to innovation in the field of medical

devices. Geneva: World Health Organization, 2010.

91. World Bank. An overview of medical device policy and

regulation. Washington, DC: World Bank, 2007.

92. van Gemert-Pijnen JE, Wynchank S, Covvey HD, et al.

Improving the credibility of electronic health technologies.

Bull World Health Organ 2012; 90: 323–323A.

93. Wootton R, Geissbuhler A, Jethwani K, et al. Long-running

telemedicine networks delivering humanitarian services:

experience, performance and scientific output. Bull World

Health Organ 2012; 90: 341D–347D.

94. Piette JD, Lun KC, Moura LA Jr, et al. Impacts of e-health

on the outcomes of care in low- and middle-income coun-

tries: where do we go from here? Bull World Health Organ

2012; 90: 365–372.

95. World Health Organization. Local production and technol-

ogy transfer to increase access to medical devices. Geneva:

World Health Organization, 2012.

96. World Health Organization. Compendium of innovative

health technologies for low-resource settings. Geneva:

World Health Organization, 2014.

97. Brinton TJ, Kurihara CQ, Camarillo DB, et al. Outcomes

from a postgraduate biomedical technology innovation

training program: the first 12 years of Stanford biodesign.

Ann Biomed Eng 2013; 41: 1803–1810.

98. Rice University, Rice 360 Institute for Global Health Tech-

nologies, 2016. [Online]. Available: http://www.rice360.

rice.edu/.

99. Som A, Charanya T, Linderman SW, et al. Bridging the gap

between invention and commercialization in medical

devices. Nat Biotechnol 2014; 32: 1063–1065.

100. World Bank. World Bank open data. Washington, DC:

World Bank, 2015.

101. The United Nations. The Millenium Development Goals

report. New York: The United Nations, 2015.

102. Victora CG, Requejo JH, Barros AJD, et al. Countdown

to 2015: a decade of tracking progress for maternal, new-

born, and child survival. Lancet 2016; 387: 2049–2059.

103. UN Commission on Life-Saving Commodities for Women

and Children, UN Commission on Life-Saving Commodi-

ties for Women and Children; Commissioner’s Report. New

York: United Nations, 2012.

104. World Health Organization. Interagency list of medical

devices for essential interventions for reproductive, mater-

nal, newborn and child health. Geneva: World Health Orga-

nization, 2015.

105. United Nations. Outcome document of the Third Interna-

tional Conference on Financing for Development – Addis

Ababa Action Agenda. New York: United Nations, 2015.

106. Policy Brief. Local production for access to medical

products developing a framework to improve public health.

Geneva: World Health Organization, 2011.

107. Local production for access to medical products: develop-

ing a framework to improve public health. Geneva: World

Health Organization, 2011.

108. World Health Organization. Towards improving access to

medical devices through local production phase II: report of

a case study in four Sub-Saharan countries. Geneva: World

Health Organization, 2016.

109. Masum H, Chakma J, Simiyu K, et al. Venture funding for

science-based African health innovation. BMC Int Health

Hum Rights 2010; 10(suppl 1): S12.

110. Reddy P. Global innovation in emerging economies. New

York: Routledge, Taylor & Francis Group, 2011.

111. Waning B, Diedrichsen E, and Moon S. A lifeline to treat-

ment: the role of Indian generic manufacturers in supplying

antiretroviral medicines to developing countries. J Int AIDS

Soc 2010; 13: 35.

112. Jarosławski S and Saberwal G. Case studies of innovative

medical device companies from India. BMC Health Serv

Res 2013; 13: 199.

113. Al-Bader S, Frew SE, Essajee I, et al. Small but tenacious:

South Africa’s health biotech sector. Nature Biotechnol

2009; 27: 427–445.

114. Fogel R and Limson J. Developing biosensors in developing

countries: South Africa as a case study. Biosensors (Basel)

2016; 6: 5.

115. World Health Organization. Pharmaceutical production and

related technology transfer. Geneva: World Health Organi-

zation, 2011.

116. Pallas SW, Nonvignon J, Aikins M, et al. Responses to

donor proliferation in Ghana’s health sector: a qualita-

tive case study. Bull World Health Organ 2015; 93:

11–18.

117. Caldwell A, Young A, Gomez-Marquez J, et al. Global

health technology 2.0. IEEE Pulse 2011; 2: 63–67.

118. Thorsteinsdottir H, Ray M, Kapoor A, et al. Health biotech-

nology innovation on a global stage. Nat Rev Microbiol

2011; 9: 137–143.

119. Samb B, Evans T, Dybul M, et al. An assessment of inter-

actions between global health initiatives and country health

systems. Lancet 2009; 373: 2137–2169.

120. World Health Organization. African partnerships for patient

safety. Geneva: World Health Organization, 2009.

Abbas et al. 13

121. Bhan A, Singh JA, Upshur RE, et al. Grand challenges in

global health: engaging civil society organizations in bio-

medical research in developing countries. PLoS Med 2007;

4: e272.

122. Crisp N. Mutual learning and reverse innovation – where

next? Global Health 2014; 10: 14.

123. Rottingen JA, Chamas C, Goyal LC, et al. Securing the public

good of health research and development for developing

countries. Bull World Health Organ 2012; 90: 398–400.

124. Juma C. Biotechnology in a globalizing world: the coevolu-

tion of technology and social institutions. BioScience 2005;

55: 265.

125. Meir A and Rubinsky B. Distributed network, wireless

and cloud computing enabled 3-D ultrasound; a new

medical technology paradigm. PLoS One 2009; 4:

e7974.

126. Mair FS, May C, O’Donnell C, et al. Factors that promote or

inhibit the implementation of e-health systems: an explana-

tory systematic review. Bull World Health Organ 2012; 90:

357–364.

127. Lewis T, Synowiec C, Lagomarsino G, et al. E-health in

low- and middle-income countries: findings from the center

for health market innovations. Bull World Health Organ

2012; 90: 332–340.

14 Nanobiomedicine