There is increasing concern globally about the enormity of the threats posed by antimicrobial resistance (AMR) to human, animal, plant and environmental health. A proliferation of international, national and institutional reports on the problems posed by AMR and the need for antibiotic stewardship have galvanised attention on the global stage. However, the AMR community increasingly laments a lack of action, often identified as an ‘implementation gap’. At a policy level, the design of internationally salient solutions that are able to address AMR’s interconnected biological and social  dimensions is not straightforward. This multidisciplinary paper responds by asking two basic questions: (A) Is a universal approach to AMR policy and antibiotic stewardship possible? (B) If yes, what hallmarks characterise ‘good’ antibiotic policy? Our multistage analysis revealed four central challenges facing current international antibiotic policy: metrics, prioritisation, implementation and inequality. In response to this diagnosis, we propose three hallmarks that can support robust international antibiotic policy. Emerging hallmarks for good antibiotic policies are: Structural, Equitable and Tracked. We describe these hallmarks and propose their consideration should aid the design and evaluation of international antibiotic policies with maximal benefit at both local and international scales. The global crisis of antimicrobial resistance has led to a proliferation of expert reports and national and international antibiotic action plans.Implementing international antibiotic policy that is meaningful in different social, cultural and economic contexts continues to prove challenging.Our multidisciplinary analysis has identified four critical challenges of metrics, prioritisation, implementation and inequality for international antibiotic policy-making.We propose a corresponding SET of basic hallmarks of good antibiotic policy, which we define as Structural, Equitable and Tracked.Our SET of hallmarks can orientate disciplinary debates and provide a framework for developing robust international interventions.Since their introduction in the 1930s, antibiotics have acquired infrastructural importance in global health and food production.Over the past decade, rising concern about AMR has highlighted the need for collective action to protect our antibiotic ‘commons’.We propose a new wide-angle approach to AMR-focused antibiotic regulation. Two basic questions guide our reflective process: (A) Is a universal approach to AMR policy and antibiotic stewardship possible? (B) If yes, what hallmarks characterise ‘good’ antibiotic policy?et al have proposed three Rs for antimicrobial development).19To answer these questions, we have developed an innovative heuristic evaluation framework, which accounts both for AMR’s biological and social facets. Our approach was informed by the numerous national and international reports proposing various principles for antibiotic policy-makingApplying this approach to AMR and antibiotic policy, our collaborative multidisciplinary analysis employed a three-stage evidence gathering, evaluation and consultation process , which cBox 1Following a 2018 Social Science and antimicrobial resistance (AMR) Research Symposium at the British Academy in London,Identified policy challenges and core hallmarks of successful intervention informed a preliminary paper, which was circulated among correspondents and attendees of a multidisciplinary 2-day workshop in London in March 2019.During presentations, small group breakout sessions, and group discussions, participants reflected on the preliminary paper’s four identified problem areas for antibiotic regulation: (A) metrics ; (B) prioritisation (prioritising specific forms of antibiotic use over others); (C) implementation ; (D) inequality .resilience of health and food systems to diminish the need for antibiotics; (3) be responsive to evolving knowledge regarding AMR and (4) relational in its acknowledgement of differing local challenges and capacities.There was agreement on these interlinked problems but the four provisional hallmarks proved more contentious: (1) antibiotic policymaking should take into account antibiotics’ infrastructural relevance in medicine and food production; (2) should increase the microbial status quo. Key to more effective policymaking has to be an acknowledgement of antibiotics’ primary utility for global health and food production, which consists in their ability to reduce mortality and morbidity resulting from treatable infections. To preserve this utility, the overriding aim of any antibiotic policy must therefore be (1) to maximise and maintain access to effective treatments for infections, which includes the development of new treatments—while (2) reducing the need for antibiotic use by preventing infections, reducing antibiotic dependencies in healthcare and food systems, and minimising the environmental load of antibiotics and resistant bacteria.Participants agreed that there was no single solution to AMR but felt that hallmarks needed to be integrated and go beyond preserving the A refined version of new Structural, Equitable, Tracked Hallmarks was circulated among correspondents and participants, who were invited to be coauthors on the paper.SET can orientate disciplinary debates and provide a framework for robust international interventions.10 20 21We believe that the resulting heuristic compass based first on the identification of central challenges of antibiotic policy-making  and second on the formulation of a corresponding Structural, Equitable and Tracked (SET) of hallmarks of good antibiotic policy, which we define as Despite long-standing regulation attempts, there remains substantial uncertainty about basic metrics surrounding antibiotic usage and AMR as well as about how to correlate measurements in a way that can inform meaningful policy formulation at the national and international levels.22Since the first warnings about ‘drug fastness’ in microorganisms in 1907,25–27Internationally, the establishment of WHONET (est. 1989) and WHO’s Global Antimicrobial Resistance Surveillance System  marked important efforts to standardise AMR reporting in humans and make data comparable.Capturing relevant data on antibiotic use to inform AMR efforts has its own challenges. Starting in the 1990s, various high income countries (HICs) began to compile antibiotic usage data.42Correlating usage and AMR data is even more challenging. In its 2018–2019 report, the English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) showed a significant reduction in antibiotic prescriptions but an increase in antimicrobial-resistant infections for the seven priority bacterial pathogens reported.45–47MCR-1 gene.Escherichia coli in China in the mid 1980s.Understanding what the implications of specific forms of antibiotic usage  in different environments are for AMR and health outcomes is similarly crucial for policy formulation. Rising numbers of point prevalence studies and whole-genome sequencing are enhancing our knowledge of drivers and variations of AMR over time and in different areas across the world.Accessed as first-line narrow-spectrum treatment for particular conditions, and those with higher risks of becoming resistant that should be used Watchfully and those that should be Reserved for last-line treatment.66 67While uncertainty remains about the degree to which interventions will be effective, reducing the overall amount of antibiotics used in health and animal and plant production systems is a key component of most AMR action plans.Staphylococcus aureus and E. coli may or may not be causing disease, and therefore, their measurement without corresponding disease burden data might be misleading.Alongside improved usage data, deciding which microbes, resistance genes and AMR reservoirs to monitor in medical, animal and plant production, and environmental settings is similarly important for the formulation of meaningful policy interventions. For humans, WHO published a list of priority pathogens to monitor and target with antibiotic development efforts in 2017.Discussed in more detail below (see Tracked), one recently proposed solution for human health might be to integrate AMR and infection burden measurements by tracking two priority organisms in bloodstream infections as part of United Nations (UN) Sustainable Development Goal (SDG) 3.d.1. This new AMR-specific SDG could help build laboratory capacity in resource-poor settings and spur the development of further integrated AMR-specific metrics. Another approach might be to strengthen point prevalence studies for specific sentinel organisms in LMIC settings.The described temporal and contextual challenges of defining resistance, measuring antibiotic usage in relation to AMR and concerning which microbes to focus on also raise important questions when it comes to defining benchmarks or key performance indicators (KPIs) for policy initiatives: how far should antibiotic sensitivity be restored or preserved for a measure to be considered successful? Should the performance of a policy be linked to its reduction of antibiotic usage or should the KPI be demonstrated impact on human health? Should success be defined as the stabilisation or decline of AMR in specific culturable pathogens? Given the mobility of resistance genes and the One Health dimensions, should a metric of success be the abundance or prevalence of a particular resistance gene in the wider environment, determined through quantitative PCR methodsOveremphasis on surveillance data itself can serve to obscure different regional capabilities, underlying political interests and competing needs in animal and human medicine.Spatial: since the 1940s, regulators have tried to protect important antibiotics by restricting their use,mcr-1 gene on transferable plasmids in bacterial isolates from Chinese pigs that polymyxins were recategorised as highest priority CIAs in 2016, received specific restriction recommendations from OIE, and were banned from use as growth promoters in China and Brazil.57 60 75The same problems of spatial prioritisation hold true in animal and plant production.Temporal: another challenge of prioritisation regards the inevitable temporal conflict between acute healthcare needs and the future-focused dimensions of antibiotic stewardship.104Answers to this temporal dilemma vary and reflect the perceived severity of need, cultural preferences for specific forms of use, and economic considerations. In some cases, the potential longer-term risk to public health of antibiotic resistance has been favoured over immediate clinical needs.34 77 107A third fundamental challenge for antibiotic policy-making concerns the formulation of binding international agreements that can still be implemented flexibly in different settings.82 112 113Using an integrated political, economic, sociological, technological, ecological, legislative and industry framework, reviews of national action plans proposed after the 2015 Global Action Plan on Antimicrobial Resistance have warned of continuing gaps in applying international concepts of stewardship at the national level.34 120However, so far, enactment of proposed measures has been fragmentary34 77One of the most significant challenges facing international antibiotic policy and global health frameworks more widely are significant levels of inequality between and within HICs and LMICs. These inequalities reflect historically uneven social and political opportunity as well as distribution of economic resources and disease burdens. Inequality has large implications for ways priorities are made and implemented in relation to antibiotics. Recognition of these inequalities challenges forms of policymaking that focus on metrics of drug reduction alone (see Metrics and Implementation above) or prioritise protection of HIC hospital antibiotics over LMIC needs for access to antibiotics and protein production.The unevenness of social and political opportunities affects who can make or demand policies. At the international level, the historical dominance of HICs on relevant health bodies and many funders’ and high-level meetings’ location in HICs has led to a relative absence of the voices of some of the most affected LMIC stakeholders.Answering these questions is important. In the case of drug development, historical priority setting has been HIC-centric due to the greater profitability of high-income markets (with a particular emphasis on the most lucrative US market) and differing regional risk priorities.Over time, decontextualised international decision making can result in policies that prioritise HIC-centric stewardship interventions like targeted drug restrictions that may prove deleterious in LMICs where infection risks are markedly higher and different.10 112Similar constraints are true for animal health which is related to issues such as food safety, food security and animal welfare. Many national and international action plans invoke enhanced biosecurity facilities, vaccination or good husbandry practices as a means to avoid unnecessary non-human antibiotic use, but they rarely set these measures as (funded) priorities contrary to raising awareness, developing surveillance or promoting responsible and prudent use, or they risk assuming inappropriate livestock production and disease management approaches in settings where economic and microbiological risks are manifestly different.The four biosocial challenges of metrics, prioritisation, implementation and inequality require a holistic response from international antibiotic policy that is ambitious enough to improve the status quo but concrete and evocative enough to be an effective guide. Because such policies are enacted within a complex ecosystem, a broad perspective needs to inform their design and deployment to maximise effectiveness and minimise unintended consequences. It is this broad heuristic perspective, incorporating One Health, spatial, temporal and ethical dimensions that underlies the three interlinked SET hallmarks proposed here .1. Structural: International antibiotic policies should recognise and respond to the multiple aspects of global antibiotic infrastructures.Historically, there has been a tendency to make AMR manageable by compartmentalising problems and blaming individuals for drug overuse instead of the underlying social, political and economic factors driving antibiotic demand and dependencies (see Metrics and Prioritisation).74 141 142Successful antibiotic stewardship cannot be narrow and divorced from the social and environmental contexts in which use is taking place. More effective international policy requires the abandonment of regulatory silos, as well as the adoption of context-sensitive models. It requires a broad structural approach to reforming not only the international antibiotic supply chain (drug producers) but also wider contributing global and regional consumption patterns  as well as associated socio-structural factors  and environmental factors .As evidenced by recent successes in HIC animal production and health systems, jointly focusing on preventing disease with vaccines and improved welfare, updating the design of surveillance, hospital, animal housing systems and modifying antibiotic-seeking behaviour by patients and animal and plant producers can reduce antibiotic dependencies.20 127 146 1472. Equitable: To be impactful globally, international antibiotic policies must recognise and respond to the unevenness in contributions towards and ability to tackle AMR while aiming for an equitable future for antibiotics regardless of where they are deployed. Historically, inequality and the difficulty of uniform policy implementation across HICs and LMICs have been major obstacles for international antibiotic reform .Because antibiotic effectiveness is a time-limited global common pool resource and even robust national responses offer little protection from the global circulation of AMR genes and organisms, the sustained pooling of international resources is an essential prerequisite to overcome identified challenges. Similar to climate change, some countries have a greater differentiated responsibility to contribute resources to this common pool than others.48 119 149 150Whether action is justified on the basis of historical usage, collective responsibility, obligations towards future generations, or enlightened self-interest, any international policy framework will have to include long-term financial and political HIC and MIC commitments to support antibiotic sensitive interventions in resource-poor communities. In LICs, antibiotic sensitive international support could centre on building human and infrastructural capacity by educating and employing more medical and veterinary professionals,Well-designed structural and equitable international antibiotic policies can generate a global win-win.119 123Because of its structural dimensions, the lack of an easy target and a dysfunctional commercial research and development pipeline for new antibiotics,3. Tracked: Progress towards structural and equitable antibiotic policies has to be tracked to ensure ongoing effectiveness of interventions, promote integration of international efforts and motivate sustained commitment of donors and funding recipients. While a regular independent international stocktake could help ensure that policy interventions remain coordinated, equitable and up to date,Achieving effective tracked interventions requires a unifying global set of multifactorial metrics. To enable the rigorous evaluation of policies, multifactorial metrics need to simultaneously take into account antibiotic access, AMR and stewardship, but avoid rewarding short-termist gaming such as relabelling disease definitions, disincentivising healthcare-seeking behaviour and decontextualising surveillance .155In addition to drawing on multifactorial metrics, policy tracking should aim to integrate metrics across domains: taking into account the legacies of pre-existing interventions, improving knowledge integration across One Health sectors and incorporating knowledge generated in other geographical and social contexts. Enhancing the integration of international knowledge gathering will strengthen regionally nuanced decision making. Since the 1940s, successive generations of regulators have tried to manage the antibiotic commons by focusing on one form of intervention like ‘rational’ antibiotic use, reducing antibiotic use via statutory bans or non-statutory incentives and replacing antibiotics . However, lack of cross-sectoral and international integration meant that benefits were often short-lived and had little effect on global drug usage or AMR.Developing multifactorial and integrated metrics will achieve little if global AMR and usage data continues to be generated and made available unevenly. Equitably boosting laboratory and data analysis capacity is a prerequisite for strengthening the ability of those on the front lines of human, animal and plant health to devise their own solutions and generate accurate data for the global community. For example, in 2010, the Danish Yellow Card Initiative required farmers and veterinarians to track and record on farm antibiotic use. The initiative complemented low-granularity sales data and helped respective communities better understand what they were doing and grow support for stewardship efforts.The past eight decades have seen antibiotic policy-makers struggle to overcome problematic metrics, narrow prioritisations, implementation deficits and global inequalities. The need for integrated architectures that act across existing silos to push evidence into action on AMR is being met through United Nations mandated mechanisms.Policies that take into account antibiotics’ SET have the greatest potential to sustainably adapt the way the global antibiotic commons are managed and accessed. As highlighted in our ideal-type example of multifactorial metrics and equitable capacity building in global food production , SET polIf the ultimate goal of antibiotic policy is to reduce mortality and morbidity resulting from treatable infections, then we need to adapt our food and health systems to provide optimal access to effective antibiotic interventions when they are needed—and simultaneously reduce the need for these interventions. This dual approach requires polices that not only focus on ‘quick fixes’AMR is not a problem to be solved but a phenomenon to be continuously managed. Individual policies may not address all identified problem areas or integrate each of our three intervention hallmarks. However, we believe that our multidisciplinary SET of hallmarks can serve as a compass to critically evaluate and improve antibiotic policy in the present and for decades to come.


A wide range of analytical methods applied to urban systems address the modeling of pedestrian behavior. These include methods for multimodal trip service areas, access to businesses and public services, diverse metrics of “walkability”, and the interpretation of location data. Infrastructure performance metrics in particular are an increasingly important means by which to understand and provide services to an urbanizing population. In contrast to traditional one-size-fits all analyses of street networks, as more detailed pedestrian-specific transportation network data becomes available, the opportunity arises to model the pedestrian network in terms of individual experiences. Here, we present a formalized and city-scale framework, personalized pedestrian network analysis (PPNA), for embedding and retrieving pedestrian experiences. PPNA enables evaluation of new, detailed, and open pedestrian transportation network data using a quantitative parameterization of a pedestrian’s preferences and requirements, producing one or more weighted network(s) that provide a basis for posing varied urban pedestrian experience research questions, with four approaches provided as examples. We introduce normalized sidewalk reach (NSR), a walkshed-based metric of individual pedestrian access to the sidewalk network, and sidewalk reach quotient (SRQ), an estimate of inequity based on comparing the normalized sidewalk reach values for different pedestrian profiles at the same location. Next, we investigate a higher-order and combinatorial research question that enumerates pedestrian network-based amenity access between pedestrians. Finally, we present city-scale betweenness centrality calculations between unique pedestrian experiences, highlighting disagreement between pedestrians on the “importance” of various pedestrian network corridors. Taken together, this framework and examples represent a significant emerging opportunity to promote the embedding of more explicit and inclusive hypotheses of pedestrian experience into research on urban pedestrian accessibility, multimodal transportation modeling, urban network analysis, and a broader range of research questions. With technology’s advanced ability to track mobility and sense environmental factors, evidence is accumulating that individuals do not always follow the shortest path, whether in private vehicles –4 or usiaggregated patterns of human mobility, primarily in the form of scaling properties and power laws; these suggest that certain stochastic processes can be used as model proxies of aggregated human mobility patterns [In a diverse array of applications such as optimization of transportation systems , 7, pathpatterns –18. HoweModeling pedestrian travel modes presents a particular challenge, then, given heterogeneity in personal abilities, travel purpose, and preferences. Such heterogeneity creates a wide spectrum of personal costs to utilizing any edge, node or subgraph of the overall pedestrian transportation network. Pedestrian-related challenges faced by urban and transportation planners are often treated with a myopic focus on a single urban problem, or transit service, or sidewalk issue, rarely addressing this variability. For example, traditional methods for studying neighborhood spatial accessibility (measuring the ease with which residents can access community amenities) display aggregation error effects and severe biases because they ignore the travel network altogether , assuming pedestrians mobilize only in the road network, or aggregating entire neighborhoods or blocks into single points of origin , 20. DesNetwork-based pedestrian access analyses are dominated by the use of a street network as the primary data layer and model pedestrians as lacking individual constraints when traversing network elements. Such approaches overlook known diversity in pedestrian experiences, e.g.,, disability populations, but are often the only practical and scalable means by which to evaluate pedestrian access due to a dearth of (1) well-annotated pedestrian transportation networks and (2) a representative enumeration of pedestrian navigational requirements. Consequently, research into pedestrian access has focused on enumerating and visualizing a handful of infrastructure elements at city-scale , small-sThe confluence of detailed pedestrian network data and characterizations of pedestrian preferences provide the opportunity to include pedestrian needs and considerations that have otherwise been historically overlooked. Omnipresent constraints on pedestrian mobility, such as those reported by wheelchair, walker, or white cane users, can be reformulated as a set of profiles of pedestrian mobility by which to evaluate a given pedestrian network, improving inclusivity in existing analyses and potentially framing new avenues of investigation. Conditional constraints, like those that arise when pushing a stroller, are amenable to the same paradigm.The need to incorporate a diversity of concerns, interpreting a single network according to a wide set of PMPs, as well as efficiency in collecting data, calls for the publication of pedestrian networks that, rather than embedding subjective interpretations a priori, are characterized by an increasingly large set of physical or legal metadata. For example, some pedestrian network mapping approaches embed evaluations of wheelchair accessibility directly in network elements , whereinHere we propose the use of pedestrian mobility profiles (PMPs) where an individual (or a subpopulation) might be represented as a vector of cost parameters determining composite internal costs of travel through particular environments. The profiles are used as a parametric expression of factors and weights of factors that impact route choice and traversal through pedestrian paths. This work presents a general framework, Personalized Pedestrian Network Analysis (PPNA), as a mechanism of integrating pedestrian mobility profiles into route forecasting over large-scale pedestrian networks. We demonstrate several network analyses in which pedestrian mobility profiles can significantly alter optimal routes and even graph properties . Additionally, by exploiting the variation among pedestrians and PMPs, we can examine pedestrian accessibility questions at large-scale via comparative analyses of graphs and subgraphs that result when different pedestrian mobility profile traversals are superimposed on the same urban pedestrian graph. For example, we can compare the graph with costs evaluated by imposing the pedestrian mobility constraints of an individual with mobility limitations to the graph evaluated by imposing a PMP with no constraints other than preference for shortest travel time in order to identify subgraphs of the urban network. These comparative analyses help us answer, in a consistent and equitable manner, questions about neighborhood spatial accessibility or access to transportation that have hitherto, in real-world applications, been conducted using survey or GPS data at limited sample sizes and travel range.This work is organized as follows. After addressing materials and methods, we introduce the main concepts of Personalized Pedestrian Network Analysis (PPNA) by presenting pedestrian mobility profiles and how network evaluations arise from calculating the costs of traversing graph components conditioned on a pedestrian mobility profile. We then illustrate the wide applicability, nuanced analytic contributions, and diversity-enhancing properties of the PPNA approach with a series of graph-analytic examples that highlight (1) interrogating pedestrian network walksheds, (2) equity in access to pedestrian spaces, (3) equity in access to public amenities and services, and (4) the identification of central network corridors that are distinct between individual pedestrians.Pedestrian and street network data were retrieved from the OpenSidewalks Project , which pThree pedestrian profiles, individualized network traversal parameterizations of the pedestrian experience, are used throughout this study as exemplars: a normative walking profile, a manual wheelchair profile, and a powered wheelchair profile. All three are stereotyped and do not adequately capture the diversity in pedestrian experience and requirements within each group, and this paper will precede specific profiles with the word “stereotyped”. The stereotyped normative walking profile is parameterized as having no restrictions when traversing the pedestrian network and can also be considered the more typical representation of pedestrian movement within the literature: a pedestrian who moves at constant speed and can use all sidewalks and crossing locations. The stereotyped manual wheelchair user represents an individual who requires lowered curbs when crossing the street and who cannot ascend inclines greater than 8% or descend slopes greater than 10%. The stereotyped powered wheelchair user represents an individual who requires lowered curbs when crossing the street and who cannot ascend inclines greater than 10% or descend slopes greater than 12%. These correspond roughly to pedestrian preferences reported in previous informal interviews of pedestrians who use these devices and to Americans with Disabilities Act (ADA) guidelines on access ramps. Again, each profile is a known stereotype; for instance, some manual wheelchair users indicated no concerns about climbing much steeper inclines than most powered wheelchair users and indicated a willingness to traverse any raised curb.We first describe a general-purpose framework for routinely bridging informational gaps in pedestrian access: personalized pedestrian network analysis PPNA, . PPNA siTransportation network data, including a pedestrian network, consist of graph structures derived from spatial relationships. In personalized pedestrian network analysis (PPNA), an edge represents a segment of a pedestrian path, and a node represents a potential “decision point,” i.e., a point where pedestrian paths meet . If two nodes are described as u and v, respectively, an edge connecting them can be described as , typically a traversable path segment in spatial networks. Path metadata can be stored along with the barebones graph description of an edge, represented as the triple , with d being any set of associated metadata such as steepness, path width, or surface composition. Because traversal will frequently vary depending on the direction of travel , personalized pedestrian network analysis reinterprets a detailed asset-level description of a pedestrian network in which there is typically a single data object representing an edge and then derives a directed multigraph. A multigraph, which can have multiple edges with the same start and end nodes, is favored over a graph in order to realistically account for branching and joining of alternative pedestrian paths. For example, a wheelchair ramp and a steep path may each be represented by a single edge that begins and ends at the same location. In this case, there exist two directed edges with the same abstract graphical representation, .Therefore, the most appropriate pedestrian network derivation for PPNA is a directed multigraph comprised of nodes connected by  edge triples. A PMP operates on these edge triples to derive a numerical weight of traversal, or impedance, and stores this number uniquely within the metadata d. For example, a pedestrian who has difficulty with hills may be partially described by a PMP cost function that accepts edge length and incline as inputs and yields an estimate of the time-of-travel, embedded in the edge metadata, d. Because PMPs are necessarily discrete and explicit in terms of the demographic concern(s) they describe, their routine incorporation via PPNA may serve to raise the profile of specific type(s) of pedestrians represented in a given analysis; potential limitations may be more easily recognized; and intentional oversights may be enumerated. For example, evaluating a detailed pedestrian network for regulatory compliance (such as compliance with the Americans with Disabilities Act) may be explicitly formulated as a highly-constrained PMP that rejects any network elements that present out-of-compliance barriers or infrastructure by assigning an infinite edge weight. This PMP would not necessarily represent any living pedestrian, but instead it would represent a theoretical floor of access that explicitly prioritizes a wide set of pedestrians. Under such a formulation, it becomes immediately clear that other concerns have been diminished: a pedestrian using crutches may actually prefer a  route other than one identified as ADA compliant, but this preference has not been accounted for. Similarly, a PMP focused exclusively on physical barriers will lend itself to access questions purely related to traversability but will necessarily lack insights into concerns that extend beyond this factor, like safety, time-of-travel, considerations of pleasantness, or fatigue. Because pedestrian needs and preferences are currently not well-enumerated, a PMP-based analysis framework emphasizes the specification of a particular research approach and who is considered.A network generated using PPNA can be analyzed in isolation or combined with higher-order, pedestrian-centric research questions. In isolation, a network interpreted through PPNA may reveal spatial or topological insights into the relationship between diverse pedestrians and their environment through direct analysis of the underlying graph structure. For example, PMP evaluation for a stereotyped manual wheelchair user who requires lowered curbs will reveal disconnected subgraphs wherever a neighborhood has poor curb ramp coverage since the PMP will generate high or infinite weights for street crossings that lack lowered curbs. These street crossing weights can be spatially summarized and compared to other metrics of potential relevance for an area of interest (AOI) to create an intersectional analysis of pedestrian access. For example, an AOI with poor link-level connectivity for a certain PMP may also coincide with demographic or economic inequalities, such as food deserts, implying greater spatial inequalities of outcome than would otherwise be recognized. A weighted graph with poor link-level connectivity for a given PMP is a network structure and can therefore also be used to pose or constrain any common graph-based research questions. For example, a research question that probes ease of pedestrian movement between different zones of activity, such as commercial-residential connectivity, can be reframed as targeted shortest-path traversals from all points of interest in one zone to all points of interest in another.These examples and considerations have elaborated on the use of PPNA as a general-purpose approach to pedestrian network modeling that can enrich existing analyses and promote a pluralistic paradigm for studying pedestrian access. The following sections highlight the application of PPNA to common questions in pedestrian access analysis and the derivation of deeper insights through city-scale interpretations of diverse pedestrian experiences.There are various interpretations or definitions of pedestrian access, with many addressing whether a given pedestrian can reach destinations of interest, potentially subject to some constraint. In this paper, we frame pedestrian access as the ability to reach or traverse elements of a pedestrian network subject to the constraint of one or more pedestrian mobility profiles (PMPs). For illustrative purposes, we emphasize use cases where pedestrians state specific mobility requirements or related mobility impairments since such concerns have been frequently overlooked in mainstream applications. Nevertheless, all of the following examples could instead be organized around PMPs evaluating other concerns like perceived trip pleasantness, fastest routes for runners given varying inclines and surfaces, expected crowdedness, and/or noise levels.A common research question in pedestrian access, particularly for transit agencies, is how to estimate a service area from which a particular asset or point of interest can be reached by pedestrians. For example, a transit agency may have a mandate to evaluate the areas, demographics, and individuals served by a particular bus line, represented as the areas reachable from one or more bus stops. However, the strategies by which a service area has been calculated vary significantly in their appropriateness and specificity to pedestrian travel. One strategy is to assume travel “as the crow flies,” or a circular buffer, in which a perfectly circular service area is generated around a point of interest . Rather than relying solely on a street network, a PPNA walkshed accounts for dedicated pedestrian paths such as sidewalks and street crossings and interprets network traversals via one or more pedestrian mobility profiles (PMPs) . WalkScore, targeted at real estate applications, famously publishes a map of “walkability” pixels, summarizing walkability as a single numeric value that applies to a large  area. While WalkScore and similar aggregated metrics of walkability have demonstrated some correlations with perceived walkability, associated pedestrian behaviors, or safety , they haThe ability to evaluate a personalized pedestrian network analysis (PPNA)-based walkshed for any point near the pedestrian network represents a data-motivated path forward for evaluating one component of walkability: sum link-level traversability of a given space. Total walkshed distance suffers from spatial and infrastructure biases, however. Compare walkshed sum distances with a single PMP for different urban spaces. One space may have a larger sum distance due solely to density of roads and infrastructure, but have less than 50% sidewalk coverage, while another space may have a low sum walkshed distance but full coverage due to having only a handful of roads. A metric of sidewalk access should be invariant to density or configuration of the street network. This can be framed as a need to normalize by an alternative hypothesis: what is the ideal expectation of sidewalk coverage given known street infrastructure?normalized sidewalk reach  distinguishing the network for which a walkshed was evaluated. The numerator is the sum total of segment lengths reachable on the pedestrian network (subject to a specific PMP), and the denominator is the sum total of segment lengths reachable on the street network according to a permissive (normative) pedestrian profile. Normalized sidewalk reach therefore approximates the actual pedestrian network distance reachable relative to an ideal case alternative hypothesis of full coverage of accessible sidewalks and crossings. A regularization term of ½ is introduced to account for the expectation that each street could have a maximum of two sidewalks. A given normalized sidewalk reach value represents the relative ability of a particular pedestrian (represented by a PMP) to access a pedestrian network similarly to an idealized, pedestrian-accessible street network. A value of 0 would indicate a street without sidewalks, a value near 1 would indicate similar accessibility between the sidewalk and street networks, and an intermediate value would indicate partial  accessibility of the sidewalk network.Accounting for these challenges, we introduce a normalized, infrastructure-specific metric of sidewalk network accessibility, lk reach . Normali.A normalized sidewalk reach value neither represents nor attempts to represent a general-purpose metric of “walkability”. Instead, it serves as an alternative metric of access to the sidewalk network that could be incorporated into a downstream walkability analysis. The development of normalized sidewalk reach is a direct consequence of applying and interpreting the PPNA approach to understanding pedestrian networks, entirely contained within the methodology.Equity in pedestrian access is of primary importance for regulatory, urban analytic, and advocacy concerns. For many research questions, the difference in outcome between classes or groupings of pedestrians is of primary interest, not just the raw access metrics for a single definition of the pedestrian experience. For example, city planners are often tasked with prioritizing equitable outcomes for infrastructure investment that weigh not just the state of infrastructure for an area of interest, but equity concerns regarding demographics. Such planning decisions must also often weigh the expected cost of development since complex funding models may make improving infrastructure in areas with the lowest need and equity concerns cheaper. Rather than relying on human practices to manage such complexity, the introduction of metrics of pedestrian access equity could assist in such decision-making processes.sidewalk reach quotient, that compares pedestrian network walksheds between pedestrian mobility profiles.In Given a quantitative metric based on a single pedestrian mobility profile, a derivative personalized pedestrian network analysis equity metric can be defined as any numerically valued function that compares values of this metric based on at least two different mobility profiles. Two obvious equity metrics would be the absolute difference between access metrics and the quotient of one metric divided by another, creating a factor of comparison. An access difference metric in this context would always be framed in units of the pedestrian access metric, corresponding to distance in the case of a walkshed metric or unitless for normalized sidewalk reach. Because a numerical difference value must be carefully interpreted in terms of the units of the associated access metric, sidewalk reach quotient (SRQ) is a factor-based metric of pedestrian equity. Specifically, sidewalk reach quotient is defined as the numerical value produced by dividing the normalized sidewalk reach for one PMP by that of a different PMP, holding the on-network starting position constant. Unless otherwise noted, PMP used for the denominator is a normative (least-constrained) pedestrian mobility profile  and Eq 2. The formulation of sidewalk reach quotient.As demonstrated in In earlier sections, walksheds  were used to evaluate access to pedestrian infrastructure, producing a quantitative means to evaluate pedestrian sidewalk access without concern for reaching or embarking from a particular amenity or activity. Applying the PPNA framework to questions of access to amenities, more typical pedestrian access questions can be evaluated at scale while representing the diversity of pedestrian needs. In addition to the expected inequities in access to public amenities, this analysis provides a means by which to quantify absolute access and service levels by neighborhood and district. Thus, by incorporating PPNA into amenity access, researchers can determine differential access to services.Many network-based research questions attempt to quantify the importance of specific network (graph) elements such as graph connectivity, identifying the highest-degree node, and centrality, i.e., how frequently a given network node or edge appears under a given traversal consideration. For example, street network centrality has been used to drive research questions concerning the impact of transportation network topology on economic activity .It is not feasible to enumerate all means by which personalized pedestrian network analysis (PPNA) can be applied to these graph analytic approaches. Instead, this section presents illustrative examples of outcomes produced by applying PPNA to common metrics of link-level edge importance. First, we identify graph connectivity as a simple yet revealing analysis on urban spaces, demonstrating the extent to which an urban space becomes disconnected into impassable (for pedestrians) islands based on PMPs. Then, we evaluate betweenness centrality at city-scale for varying PMPs, identifying the best-connected infrastructure for traversal by different populations.A fundamental property of any graph is connectivity, i.e., whether all components are connected or whether there are disconnected subgraphs. The pedestrian transportation network gathered for the city of Seattle is a connected graph by default, but when evaluated by a pedestrian mobility profile that requires lowered curbs to cross the street, it rapidly splinters into a large number of pedestrian access “islands” . WithoutA graph analytic approach to identifying potentially important or otherwise explanatory network elements is betweenness centrality: given an all-shortest-paths analysis of graph nodes to all other graph nodes , edge betweenness centrality counts the number of shortest paths that use a particular network edge . In this framing, the units compared to determine what a “shortest” path entails are conditioned on the cost function used to evaluate each network edge and can represent units of time, distance, or a more complex combination of concerns. Alternative PMPs produce starkly different patterns in centrality, suggesting infrastructure that may be of vastly differential utility depending on pedestrian mobility concerns. City planners or permitting authorities will not recognize such potential bottlenecks or important corridors without quantitative approaches that compare mobility or other pedestrian concerns. For example, a highly central corridor of the pedestrian transportation network for stereotyped wheelchair users in the Southeast corner of the area of interest running South to North is not present for stereotyped normative pedestrians. As a path connecting residential zones to a major school and a commercial district, it may be the only direct path available for wheelchair users to access these amenities, and any disruption to the sidewalk network  may produce a highly inequitable outcome that would otherwise be overlooked.In the preceding sections, we presented illustrative cases addressing the utility of imposing parameterizations of the pedestrian experience on a detailed, city-scale pedestrian network for downstream analysis. In some cases, this approach was developed in order to create direct scoring metrics of accessibility , or used to constrain common network metrics , demonstrating amenability to being routinely incorporated into urban analysis. In all scenarios, the quantitative introduction of pedestrian diversity into the analysis provided deeper insight by promoting a more detailed modeling of pedestrian concerns, highlighting exactly which pedestrian concerns were being considered (and which were not) and promoting the use of a more realistic pedestrian network from which to derive such insights.Because personalized pedestrian network analysis framework has such broad potential application for any question regarding pedestrian access, many analyses that we did not present here could be of value in future work. Linking distinct economic zones is of primary interest to transit agencies, and while neither transit stops nor their ability to connect pedestrian spaces were evaluated in this study, these research questions would be enriched by a PPNA approach. Vision Zero and other pedestrian safety efforts could be well served by more nuanced models of pedestrian behavior and would likely benefit from more varied network metadata than is currently available. There is a panoply of pedestrian concerns that are rarely evaluated but of potentially greater importance that would be appropriate for a pedestrian mobility profile and therefore a personalized pedestrian network-based analysis. The pleasantness of a pedestrian trip may factor in greenways, availability of covered walkways to avoid sun, rain, or snow and quantify them in terms of a PMP. The amenability of a space for safe and legal recreational use by wheeled sports equipment may quantify a PMP with similar infrastructural preferences for wheelchair populations, but with entirely different parameterizations. Individuals with respiratory concerns may benefit from a PMP that prioritizes indoor routes, routes known to have high-quality air purification, or those that avoid vehicular traffic. In addition, the PPNA approach could be adapted to evaluate the completeness or appropriateness of both real and planned pedestrian infrastructure projects, such as attempted implementations of the Complete Streets specification.All pedestrian access metrics explored in this work are a priori estimations of pedestrian access concerns and can be interpreted as hypotheses about potential real-world pedestrian experiences. These hypotheses should be tested against real-world data using methods like surveys, location tracking and map matching, and ethnographic practices. Aside from testing the potential validity of these pedestrian models, real-world data can drive refinement and improvement of how pedestrian concerns are modeled and how likely trade-offs are weighted. For example, in informal interviews, pedestrians with a variety of mobility concerns have communicated a willingness to attempt traversal of barriers they previously identified as impassable in order to save substantial amounts of time. Real-world pedestrian behavior will therefore certainly vary from a priori expectations and suggest what those trade-offs may be, providing an opportunity to approximate the diversity of pedestrian experience from behavioral data in a PPNA approach.The pedestrian network presented here, while at much larger scale and specificity than those previously explored, remains limited. The problem of the last 50 meters of travel remains, with the trip from primary connecting pedestrian infrastructure to a realistic destination being unspecified. When assessing access to amenities, no datasets specifying the exact entrances to those facilities or the intervening pedestrian infrastructure were available, forcing guesswork and estimations that contradict some of the core premises of a PPNA-based approach: the traversability of pedestrian infrastructure is of primary importance for evaluating access. Indoor spaces are increasingly important for urban spaces and traversable pathways, both to access amenities and as an intermediate route between destinations but are largely unmapped. Furthermore, because large-scale, detailed mapping of pedestrian spaces is an emerging phenomenon , 60, manThere is significant potential for advocacy work in elevating the importance of a diversity of pedestrian experiences. Some of the work presented in previous sections  was successfully used to advocate for providing access for disability populations to public buildings after-hours in downtown Seattle since indoor elevators connected important transit hubs but were otherwise unavailable. Prior to a data-driven formulation, these concerns could be communicated only anecdotally by individuals. However, as a human-contingent analysis of infrastructure at scale, they became vital data on which civic action was premised.


Regulatory expectations are considered, emphasizing that product development should prioritize detailed characterization of therapeutic cell populations for specific indications.Mesenchymal stem cells (MSCs) are in development for many clinical indications, based both on ‘stem’ properties (tissue repair or regeneration) and on signaling repertoire (immunomodulatory and anti-inflammatory effects). Potential conflation of MSC properties with those of tissue-derived stromal cells presents difficulties in comparing study outcomes and represents a source of confusion in cell therapy development. Cultured MSCs demonstrate significant heterogeneity in clonogenicity and multi-lineage differentiation potential. However  Variation is a fundamental concept in biology. While conservation of genes over evolutionary time spans allows for the preservation of essential processes common to all life it is variation that enables adaptation and survival. Within species, biological and behavioral traits exhibit a continuous spectrum of variation  which arWithin a clonal population of cells, variations in gene expression between individual cells arise due to both extrinsic and intrinsic factors which determine the exact profile of gene expression and biological activities . Since cThe regulatory frameworks for medicinal products, which includes cell therapies, require developers to define and produce consistently a specific product which is controlled in terms of its quality attributes. Developers need to consider how to achieve routine manufacture of safe and efficacious cell therapies when the very nature of the starting material seems to undermine this objective.et al. [Mesenchymal stem/stromal cells (MSCs) represent a significant fraction of the current efforts to develop cell-based treatments for a range of diseases. There are at present 98 clinical trials involving mesenchymal stem/stromal cells as the investigational medicinal product registered with the European clinical trials database EudraCT . The colIn this perspective we consider the impact of biological heterogeneity on some of the regulatory requirements to which MSC-based therapies are subject, and discuss how these factors might impact upon the use of MSC in regenerative medicine.in vivo [One of the most challenging aspects of MSCs is the perennial debate over nomenclature: ‘stem’ versus ‘stromal’ and thus identity. Stem cells may be defined by two broad properties: the capacity for self-renewal and symmetric and asymmetric division, through which they produce lineage-committed progenitors which ultimately differentiate into tissue-specific cells . Stem cein vivo .ex vivo culture of embryonic chick mesenchymal tissue. Similar findings were obtained using cultured cells derived from the periosteum; the author did not examine other tissues but contended that a similar approach would be suitable to assess other mesenchymal tissues. This paper was one of the first to suggest the potential for use of ex vivo culture-expanded cells to produce replacement skeletal tissues as a therapy.The term ‘mesenchymal stem cell’ originated with Caplan  followinstem cells, which combine demonstrated self-renewal with intrinsic skeletogenic differentiation potential, with stromal cells from a range of different tissue sources, both structural and nonstructural. A multiplicity of terms, each with its own implicit assumptions, has arisen, and despite repeated calls for clarity rooted in the specific biology of the cells, notably from the International Society for Cell and Gene Therapy (ISCT) [The literature abounds with descriptions apparently conflating bone marrow-derived y (ISCT)  and othey (ISCT) , many rein vivo  and mesenchymal stromal cells from multiple tissues, shown to be multi-potent via in vitro differentiation assays [The ISCT recommended a clear distinction between the bone marrow-derived self-renewing fraction with proven multi-potent differentiation n assays . Since tin vivo serial transplantation [in vitro into different lineages beyond skeletal tissues [‘MSCs’ are described in the literature in broadly two ways: firstly specifically the rare cellular component of bone marrow, proven to be self-renewing, clonogenic and capable of producing skeletal tissues only, via antation ,18. This tissues ,20. Much tissues   and that selection by CD146 expression isolates a population including clonogenic, self-renewing multi-potent cells capable of forming both bone and hematopoiesis-supporting stroma upon transplantation.The existence of a nonhematopoietic stem cell within bone marrow was confirmed via a number of key studies, summarized by Bianco : in vivoet al. [-/CD146+ cells expanded from human bone marrow establish both hematopoietic tissue and bone organoids when transplanted ectopically [In situ, CD146 expression is limited to ARCs within bone marrow sinusoid walls; these cells are endothelial marker-negative  but express markers of pericyte  and mural cell origin (NG2) [-/CD271+/CD45−/CD146−) allows in situ localization of another population of MSCs to endosteum [et al. [+/CD146-/CD73+/CD164+ phenotypic profile identifies a human skeletal stem cell (SSC) associated with growth plate rather than bone marrow, which is clonogenic in vitro and produces bone, cartilage and hematopoietic stroma in vivo. These findings mark a departure from the usual picture of bone marrow-derived MSC, in that adipogenic differentiation was not observed, and in contradiction to other studies, the SSCs lack CD146 expression which locates MSC in perivascular  sites [et al. [MSCs are an integral component of the hematopoietic niche in bone marrow ,29. The et al. . Brieflyet al. . Single ndosteum . Recentl [et al.  reportedl) sites . It is t [et al.  represenBone marrow stromal cells, traditionally isolated from marrow via plastic adherence, form fibroblastic cell colonies (colony-forming units-fibroblastic or CFU-Fs)  which foet al. [et al. [et al. [et al. [et al. [Álvarez-Viejo et al.  have higet al. ,41. Many [et al. , Calloni [et al. , Kobolak [et al.  and Sams [et al. .Any culture of stromal cells isolated from primary tissue will be a heterogeneous mixture: for example, bone marrow aspirate contains a variety of hematopoietic cells, red blood cells and stromal cells including fat cells, endothelial cells, fibroblastic cells and marrow stem/progenitor cells . The iniDonor variation is well recognized as a fundamental source of variability in MSC populations, including in growth kinetics, and thus potential yields between donors and immunomodulatory capacity . Donor aPopulations of MSC in culture will contain different proportions of true stem cells and differentiation-committed progenitors. Individual cells within a culture proliferate, differentiate and senesce at different rates, such that it cannot be accurate to represent a culture of bone marrow stromal cells as a homogeneous population of MSCs . Culturein vivo, compared with polyclonal populations, which invariably form bone upon transplantation [In vitro differentiation potential is likewise variable between individual clones: in one study >20% of clonally-derived human stromal cell strains showed tri-lineage differentiation potential to all three osteogenic, chondrogenic and adipogenic (OAC) lineages in vitro, with the majority being osteogenic-chondrogenic (OC) bi-potent clones [Single colony-derived bone marrow stromal cells vary in their potential to induce bone formation antation . In vitrt clones . This stt clones ; these dt clones .in vivo transplantation: 67% bone-forming but only 12.5% forming bone and hematopoietic tissue, and around 20% forming only fibrous tissue [in vitro than those with uni- or bi-potency [Ex vivo markers of osteoblastic phenotype  were not predictive of the in vivo bone-forming capacity. Therefore, it is of a great interest to define ex vivo molecular markers that are better at predicting the in vivo bone-formation capacity of BMSCs.Populations expanded from single colonies of human bone marrow stromal cells from a single donor show wide variation in differentiation potential following s tissue . Multi-p-potency . These s-potency . Ex vivoet al. [invitro; the other expressed increased immunomodulatory and immune defence genes and showed greatly reduced tri-lineage differentiation potential. Of note, clones from both studies all expressed a range of ‘expected’ MSC markers including CD29, CD44, CD63, CD73, CD90, CD105 and CD166 despite such large differences in differentiation potential.The preceding studies used nonimmortalized bone marrow stromal cells in extended culture, which invariably results in loss of differentiation potential . Immortaet al.  reportedin vivo or in short-term nontransformed culture, the latter being more likely to be used for production of cell therapy medicines. The preceding studies illustrate the difficulty in producing a consistent population of cells for therapeutic use. Even with tissue from a single donor, controlled culture conditions and expansion from a single cell, each clone produces a distinct population with widely different morphology, growth kinetics, gene expression profile and functional protein expression.The use of immortalization to facilitate reproducible studies on consistent cells is a valuable research tool that allows exploration of the inherent heterogeneity of MSCs but such cell lines may not reflect the natural organization or characteristics of bone marrow stromal cells either in vivo from bone marrow-derived MSC have been extrapolated to make assumptions about cultured cells. These assumptions have apparently been the basis of a rationale for clinical application of expanded MSC in a variety of therapeutic indications. These applications reflect expectations based on the current understanding of the behavior of MSCs in vitro, and suggest an assumption that properties exhibited in a culture environment will necessarily be maintained upon administration to a patient.Reporting of the isolation of stromal cells possessing multilineage differentiation capacity from a wide range of tissues including adipose, placenta, umbilical cord (UC) and dental pulp has led to a situation in which attributes observed The apparent acceptance that all tissue sources contain stem cell populations comparable to those seen in bone marrow stroma has led to a noticeable divide in published views of the use of MSC in clinical development : at one The literature clearly highlights the extensive variation among populations of MSCs whether arising from tissue source, culture conditions or population doublings, and one of the most important aspects with relevance to regenerative medicine is the extent to which a population of MSCs derived from a single donation/tissue can vary. It will be important, and also challenging, to elucidate the profiles of subsets most promising for different indications, which implies identification of subsets with relevant gene/protein expression for the intended function and ability to isolate these subsets based on accessible epitopes.The ability to culture such colonies of stromal cells from many different tissues has contributed to the expectation that multiple sources contain cell populations with analogous properties to bone marrow-derived stem cells ,20. HoweThe developmental origins of MSC may include neural crest . FurtherThe explosive growth of the MSC cell therapy industry has been based, in part, on the expectation of tissue/source equivalence, with 26% of current EU clinical trials using adipose-derived MSCs, and 30% not stating the tissue origin in the publicly accessible trial details on the EU clinical trial register EudraCT . AlthougMedicinal products, including cell therapies, are regulated on the basis of their intended therapeutic indication. That is, the applicant for a clinical trial or marketing authorization has to define what condition is to be treated or prevented, or what clinical effect the medicinal product is intended to achieve. Early in product development, there may be only prior literature, or hints from primary research, to guide identification of mechanisms that could deliver potentially useful clinical effects. These clues must ultimately be crystallized into a package of data that identifies the active moiety  and demonstrates its safety and effectiveness in the proposed clinical indication. Elucidation of relevant mechanisms of action is thus a key aspect of development of cellular therapies. While it may be almost impossible to identify all possible mechanisms, an understanding of the major properties likely to result in the intended biological activity is essential.For the medicinal product to be licensed, allowing it to become accessible to patients on a routine basis, regulatory requirements must be met. A critical aspect of development of all biological medicines is the requirement for a potency assay: one or more assays capable of confirming that the batch of product meets established specifications for relevant biological activity when compared against a reference standard or performance criterion, thus ensuring consistency of production ,75. Potein vitro and in vivo assays [Consideration of the requirement for a potency assay, or more likely a combination of complementary assays, highlights the necessity of understanding the broad mechanisms of action of the product. Immunomodulatory properties of MSC have been studied extensively in o assays . Althougo assays . Recent o assays ,81. TablIn situ differentiation into site-specific tissue for repair of tissues/organs, once a cornerstone of the MSC treatment paradigm, is increasingly rejected as evidence of lack of engraftment and persistence following intravenous or local injection accumulates, pointing to paracrine effects rather than replacement with differentiated tissue de novo for nonskeletal indications [For cellular therapies and in particular those intended for tissue repair/regeneration, there are likely to be a range of mechanisms involving secretion of trophic support molecules ,89–91. Tications ,96. Inheications . The MSCications . Immunomications  thus preications ,101. Priications . Aside fications ,104, altFor many regenerative applications, stem properties  may therefore not be relevant at all. In this vein, the concept of MSC as ‘medicinal signaling cells’ arises ,27. ProdWith a vast range of potential molecules, pathways, networks and interactions that could contribute to clinical efficacy of a MSC-based cell therapy, assessment of the means by which it achieves its effects becomes incredibly challenging. Fortunately regulators in the EU and the US do not expect fully developed potency assays as a condition of entry into clinical trials in human subjects; however a rationale to underpin the choice of indication and some evidence that the cell-based therapy can deliver relevant effects will be required before human trials begin, usually in the form of nonclinical pharmacology studies. Given the complexity of the potency issue, it is inevitable that there is a link back to identity of the cell population being developed. The identity profile needs to be defined during development, such that the impact of materials used for production, the control and consistency of processes employed can be assessed to ensure product of a consistent and relevant biological functionality can be generated. This in turn supports the production of consistent batches of cell product for the intended clinical effect: all are integrally linked . Thus unin vivo should facilitate production and clinical evaluation of cell therapies [in vitro functionality are not necessarily related to the corresponding activity in vivo. Global gene expression analysis may allow the elucidation of relationships between phenotype and function by highlighting possible relationships that are not immediately apparent [in vivo function.A more defined phenotype capable of predicting a required biological function herapies . Howeverapparent . HoweverMSCs are a major candidate for a wide range of potential therapeutic applications. Although the actual cell numbers required to treat an individual patient may vary with indication, it is certain that the overall numbers required to produce commercially and clinically viable products will necessitate effective expansion strategies. However the expansion of MSCs in adherent culture is known to result in slowing and eventual loss of proliferation  and lossThe current challenges in identification of MSCs with true stem potential means that the expanded cells administered to a patient may comprise a heterogeneous population identified only by plastic adherence and the expression of a few nonspecific surface markers. This is of particular importance in early clinical trials, in which the supporting functional evidence generated in small animal models may have been achieved with much smaller cell numbers produced via fewer population doublings: a less expanded population of MSCs will likely represent a different population with differing proliferation and differentiation capacity. Differences in administered populations may result in failure and rejection of promising therapies when results in animal studies are not replicated in early clinical trials. Although difficult to assess this directly, it is certainly the case that many successful studies in animals do not translate/have not yet translated to positive results in the clinic. Whilst regulators do not currently require cell-based products to be absolutely pure, and in any case there would be significant challenges in defining what this means in practice, certain regenerative medicine applications may benefit from use of a clonal population rather than a heterogeneous material expanded from multiple primary cells .et al. [et al. [Studies of culture methods intended to increase yields of MSCs for clinical use tend to quantify output by characterizing the expanded populations in terms of phenotype, plus occasionally morphology and immunosuppressive activity, for example, Gottipamula et al. , Haack-S [et al. . Similar [et al. . These ain vitro can be isolated from many stromal tissues. The presence of true stem cells has been demonstrated in bone marrow [ex vivo expanded MSCs. Regulatory authorities recognize the distinction between the native functions of cells and their potential uses in medicinal products. The cell therapy regulations in both the EU and the US make a distinction between cells intended to perform the same intended function as native cells and those for which the intended clinical purpose of the cells is different to that which the cells would normally perform in the body, with this so-called ‘nonhomologous use’ being regulated by medicines/biologics legislation  No 1394/2007 Article 2.1 (b) ‘Tissue engineered product’ means a product that:–contains or consists of engineered cells or tissues2.1 (c) Cells or tissues shall be considered ‘engineered’ if they fulfill at least one of the following conditions:–the cells or tissues have been subject to substantial manipulation, so that biological characteristics, physiological functions or structural properties relevant for the intended regeneration, repair or replacement are achieved. The manipulations listed in Annex I, in particular, shall not be considered as substantial manipulations–the cells or tissues are not intended to be used for the same essential function or functions in the recipient as in the donoror of cells or tissues that are not intended to be used for the same essential function(s) in the recipient and the donor;Directive 2001/83/EC Annex Part IV 2.2.(a): Somatic cell therapy medicinal product means a biological medicinal product which has the following characteristics: (a) contains or consists of cells or tissues that have been subject to substantial manipulation so that biological characteristics, physiological functions or structural properties relevant for the intended clinical use have been altered, 21 CFR 1271.10a) An HCT/P  is regulated solely under section 361 of the PHS Act and the regulations in this part if it meets all of the following criteria:…(2) The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent;The rigor applied in primary research to further elucidating the locations, properties and functions of individual sets of bone marrow stem and stromal cells, and stromal cells from other tissues, is essential to help inform selection of appropriate populations for regenerative medicine applications. There is abundant evidence that stromal cells from different tissues exhibit differences in marker profiles, gene expression patterns and propensity to differentiate into particular cell types. Inherent heterogeneity of cell populations makes characterization challenging, but developers of regenerative medicines should take into account the basic biological attributes of their chosen cell type, perhaps considering the optimum tissue source and desired functionality based on a combination of fundamental biology and understanding of the impact of processing conditions during cell expansion.in vitro differentiation assay that may have little or no specific relevance to that indication.Developers of MSC-based therapies need to be cautious in their assumptions about the identity and relevant mechanisms of action attributed to their cell population. The expression of a range of nonspecific surface antigen markers is to be expected for MSCs; in order to be relevant for regulatory identity requirements, developers should seek to identify combinations of markers more specific to the cell population produced in their particular manufacturing process. The ability of a specific cell population to deliver particular biological functionality must be explored in the context of the intended indication, and not by application of a generic We should be mindful, however, not to paralyze the field of regenerative medicine with ambitious goals that may hinder valuable clinical progress: a balance between detailed understanding of native biology and practical analysis of the cell population under development is essential. It is important to emphasize that different stakeholders will have different interests and objectives: research scientists seek elucidation of the biology of cells within their native environment; regulators require that the specific cell population, in other words, the ‘drug substance’ for clinical application is characterized, and the cell therapy community could benefit from a standard set of criteria that may be helpful in providing a baseline for comparison of results. Does it matter what we call these cells when each clinical trial application requires individual identity, cellular composition and relevant potency criteria for the cells and process under consideration for a specific indication? From a purely regulatory perspective, probably not, but in order to allow for meaningful comparisons during research we should seek clarity of terminology and descriptions, avoiding universal attribution of properties elucidated under specific circumstances.As the clinical use of MSCs increases, it would be of value to the research community to share key data. For example, publicly accessible databases such as the Stemformatics stem cell project  allow suVariation is a fundamental concept in biology.Heterogeneity arises in clonal cell populations.Potential challenges for the regulatory framework because of mesenchymal stromal cell (MSC) heterogeneity.Clinical trials in the EU are exploring the use of MSCs in a wide range of different therapeutic applications.Stem or stromal? Are the two terms conflated in the MSC literature?Definitions and additional ‘MSC’ acronyms, and the use of ‘standard’ identification criteria for cultured MSCs.Brief history of the identification and functions of MSCs within the hematopoietic niche.Phenotypic identification of a putative human skeletal stem cell.Identification of colony-forming units – fibroblastic within bone marrow stroma.Isolation and enrichment by cell surface markers.Impact of donor age, gender and tissue source.Colonies form a heterogeneous mix of cells with varying self-renewal capacity and multipotentiality, and not a population of ‘stem’ cells.Cultures expanded from single colonies demonstrate extensive heterogeneity both within and between cultures.Single clones from immortalized MSC cell lines show profoundly different gene expression profiles and differentiation capacity.Perceptions of MSC: a spectrum of approaches to their use in regenerative medicine.Equivalence of tissue sources.The potency assay – linking identity and variability to regulatory expectations.Impact of heterogeneity on cell therapy product manufacture.


Stem cell research has attracted much public and biomedical anticipation centred on the possibility of using stem cells to treat various diseases and conditions, but the number of evidence-based therapies is currently limited. Numerous commercial direct-to-consumer (DTC) businesses are nonetheless marketing experimental stem cell therapies online for myriad medical conditions and aesthetic ailments, which has attracted critique due to safety and efficacy concerns. Existing research has largely focused on the problem of unproven therapies and regulatory pathways for addressing it. The proliferation of these experimental products must also be examined, however, in the broader socio-technological context of consumer culture and changing practices of knowledge-making in the digital era. DTC stem cell therapies have emerged as a new biomedical ‘lifestyle’ product that blurs the boundaries between ‘science,’ ‘medicine,’ and ‘consumer culture.’ In using, conceptualising and marketing stem cells, commercial businesses build on and commercially co-opt alternative epistemic and ontological frames that challenge scientific medicine. They advance promissory narratives about their potential that tap on cultural aspirations around the future of medicine and health. This is key, not only for understanding how and why these therapies have proliferated but also in conceptualising what the ‘problem’ around them actually is. Yet, apart from a small number of evidence-based therapies, evidence for the effectiveness and safety of clinical applications for stem cells is currently insufficient or in the pre-clinical stage. Despite this, recent years have witnessed the global proliferation of commercial businesses providing experimental stem cell therapies that have not undergone clinical trials but are nonetheless offered by private healthcare providerset al., et al., et al., The emergence and abundance of stem cell businesses has attracted widespread condemnation from mainstream medical authorities who have issued warnings about the dangers of experimental stem cell therapies. Critical commentaries calling for stronger regulation and customer protection around such therapies have multiplied  online market of experimental stem cell therapies, in order to explore the following questions: how are ‘stem cells’ conceptualised and represented to consumers? What epistemic frames guide these conceptualisations and representations, and how do they fit within the current landscape of science, medicine, and consumer culture?Our aims are twofold: firstly, while we map the scope of the UK market, our objective is less to document the number and distribution of the businesses and more to use this mapping as background for examining how the digitally mediated market itself offers an emerging alternative discursive and epistemic sphere to conventional evidence-based medicine. Whereas existing research has primarily taken the problem around commercial stem cell therapies to be insufficient regulation, safety, efficacy, and consumer exploitation, we aim to look beyond this conceptualisation of the problem. We aim to shed new light on the techno-scientific and medico-cultural context within which the therapies have been commercialised. This is because the currently dominant framings of the problem can have the effect of constraining the scope of analysis in ways that limit our ability to properly account for the context that foregrounds how these therapies are marketed.Secondly, we aim to contribute to existing STS literature on the nature and implications of knowledge-making in the digital era. We do this by exploring how digital environments mediate the co-existence of plural knowledges and the emergence as well as commercial co-optation of alternative epistemic frameworks that challenge scientific medicine. The epistemic frames used by commercial stem cell therapy businesses exemplify a blurring of the boundaries between medicine and consumer culture. Experimental DTC stem cell therapies can be understood as a new kind of biomedical ‘lifestyle’ product that represents the fragmentation of conventional scientific authority. This perspective also broadens the scope of current discussions and debate around DTC stem cell therapies, as it offers a contextualising angle that should be accounted for in developing responses to the proliferation of experimental stem cell therapies.Digital technologies are changing how patients and consumers use, access and interpret medical information, and how they communicate about and purchase healthcare services and products Lupton, . DigitalConcurrently and relatedly, it has been argued that the ‘digital era’ in which we increasingly live is characterised by growing scepticism towards conventional scientific medicine. Top-down forms of medical knowledge production and hierarchical or clinician-centred models of the clinical encounter  are becoming increasingly contested Lupton, . This isThe emergence of DTC medicine (including stem cell therapies) is a related phenomenon. It mirrors the fragmentation of top-down forms of medical knowledge-making and pluralistic modes of health and knowledge in the digital era, but it also represents the commercialisation of knowledge pluralism. The online search technologies  medicine today. Indeed, much social analysis of DTC medicine in its many manifestations  in the digital era, Saukko et al.  have als et al., . Indeed,, et al.  argue thet al. interpretation and (promissory) uses of science in the digital era. We do this by focusing on stem cell businesses and how they configure  their products through their marketing strategies and portrayals. In particular, we build on Saukko et al.  to argueWhile there has been significant research investment in clinical applications for stem cells – indeed, the UK Clinical Trials Gateway UKCTG,  containeet al., et al., Commercial businesses, however, offer stem cell therapies for a variety of diseases and afflictions that are not offered (nor approved) by public and mainstream healthcare providers and authorities. These therapies have often not undergone clinical trials nor are they derived from the well-established treatments, but they are nevertheless accessible and marketed directly to customers via digital platforms. Digital media provide commercial healthcare providers with a marketing avenue and customer base that seems willing and able to pay for and even travel beyond borders to receive experimental stem cell therapies. Indeed, ‘stem cell tourists’ have received much commentary, especially from the perspectives of medical tourism and healthcare commercialisation in the global context  has also issued guidelines for prospective stem cell patients, instructing them to evaluate stem cell therapy providers against conventional evidence-based scientific criteria , mainstream healthcare authorities working within evidence-based epistemologies have widely condemned these therapies and the businesses providing them. The consequence has been that boundaries have been drawn between ‘legitimate’ and ‘illegitimate’ or ‘proven’ and ‘unproven’ therapies, where the boundary has primarily focused on the existence and lack thereof of evidence from clinical trials   mail-order stem cell products (e.g. cosmetics); research organisations and companies not offering therapies directly; veterinary businesses; and stem cell biobanks (e.g. cord blood and tooth).Websites of businesses meeting our inclusion criteria were downloaded using the SiteSucker application. Information including the business’ name, website URL and preliminary website content (e.g. kinds of therapies offered) were entered into a dataset. We also documented the location and number of individual facilities operated, as many businesses had a single website but multiple locations across the UK administering stem cell therapies. We produced two maps to visualise this data using the Google MyMaps tool, assigning each individual facility with a pin.We then conducted qualitative thematic analysis . Therapies based on cells from bone marrow (13) and blood (8) were also common, some advertising both. Plant stem cells (4), ‘placenta’ and ‘umbilical cord’ tissue-derived stem cells ‘harvested from sheep’ (2) and ‘autologous corneal limbal stem cells’ (1) were also marketed. Many businesses (25) did not specify the biological origins of stem cells, but made generic claims about stem cell therapy or treatment, or therapies claimed to promote or rely on stem cells. Several businesses (12) marketed stem cell therapies using proprietary technologies with labels such as ‘Lipogems’ or ‘FAMI,’ where the technologies were key to the marketing strategy. Emphasis on trademarked technologies was a notable characteristic overall in how the therapies were framed for consumers.Corresponding with Turner and Knoepfler’s  findingsWhile stem cell therapies were marketed for myriad conditions and ailments, aesthetic and what can be classed as orthopaedic interventions involving musculoskeletal issues were most common. Many advertised therapies for both musculoskeletal and aesthetic ailments or other combinations of speciality and procedures in ways that muddied conventional distinctions between cosmetic and medical interventions. Most commonly advertised were interventions usually defined as cosmetic (often marketed in combination with other therapies) (52). Musculoskeletal conditions and related pain management were also common (15). Other therapies included so-called sexual dysfunction, eye conditions, and cancers.et al.  websites and separate but overlapping clinical teams: The Regenerative Clinic  and the The overlap and shared conceptual basis between the two clinics demonstrate how the idea of regeneration is used as an interpretive frame that clusters seemingly disconnected bodily conditions under a single therapeutic paradigm, providing an alternative to conventional scientific medical practice. By marketing Lipogems as a therapeutic solution to myriad musculoskeletal and aesthetic problems, the clinics shift the epistemological and diagnostic emphasis in medicine from the conventional specialisation around an object of investigation . They direct it, instead, towards regeneration as an epistemological and methodological framework that takes primacy over the causal origin and material location of the problem treated.The centring of regeneration and rejuvenation and displacement of clinical areas and conditions of specialisation is further highlighted in the naming of businesses using this framework. In addition to the Regenerative- and Regenerative Beauty Clinics, UK-based businesses operate under names including the Rejuvenation Clinic 2018), Dynamic Regenerative Medicine , Welsh C, DynamicSome patients who have Lipogems treatment for joint rejuvenation opt to use some of the additional fat harvested for facial rejuvenation. This treatment can be done at the same time (in one procedure) and allows patients to utilise all the harvested and treated fat.Additionally, ‘some patients may opt to have more liposuction performed for aesthetic reason.’ This suggests that a customer may choose both liposuction through which stem cells are also harvested, combined with stem cell therapy using the stem cells simultaneously to treat musculoskeletal conditions and aesthetic complaints.The collapse between seemingly unrelated medical and aesthetic complaints is also exemplified by various multi-sited, combined interventions that are marketed. The Regenerative Clinic website notes that:generating a rejuvenated complexion, Stemcellation injections have a range of health-related benefits. Stem cell injections remedy fatigue and lessen age-related health problems such as high blood pressure, diabetes, hypertension, cholesterol, gastric ulcers, migraine, blood circulation disorders and arthritis.Such representations not only position stem cells as multi-site medico-aesthetic actors capable of healing all ills but also represent them as having almost magical properties that can bring about ‘the miracle of rejuvenation’  bodies in the form of stem cells.The appeal of regeneration and rejuvenation is intertwined with claims about stem cells that blur contemporary science, science fiction, and mythology. Most notable in this regard are the Genesis Clinics , which met al., as regeneration that heals and simultaneously beautifies.The above highlights how science and (consumer) culture are being blurred in the marketing of stem cell therapies. The businesses forge a marketing space for stem cell therapies as a desirable biomedical lifestyle product  problem for which new biotechnologies can offer a solution Moreira, . The Amaet al., Portrayals of stem cells’ age reversing properties tap into representations of stem cells as a miraculous creative force, but additionally depict them as the fountain of youth  that position health as something that can be acted on proactively. This includes by individuals themselves who can become agentic in managing their own health  treatments , commercial businesses position translational stem cell science and derived therapies temporally into the future. This has also characterised other new biomedical technologies  covering a wide range between well-established medical treatments and entirely un-evidenced alternative therapies, marketed based on claims about the therapies’ naturalness and future potential. The Regenerative Clinic , for exaYet, some clinics simultaneously sit at the borders between conventional and alternative medicine or merge them to construct hybrid models between conventional and alterative practice, including the Regenerative Clinic. It claims to ‘specialise in avoiding surgery whenever possible’ and states that regenerative therapies can be ‘an appropriate medical alternative to orthopaedic surgery.’ However, it also offers traditional surgical techniques and the website even includes an educational video about evidence-based medicine.Future-oriented promissory narratives allow businesses to present themselves as being at the forefront of biomedicine, enabling health consumers to be part of realising a new science of regenerative healing in-formation. They also allow businesses to position themselves as alternative to conventional medical and healthcare services that is both natural and promotes scientific advancement, including via experimental but promising new therapies.DTC marketing of experimental stem cell therapies has been considered as mainly a problem of safety and efficacy due to the therapies’ experimental nature, but the proliferation of these therapies should also be analysed in the broader context in which the therapies have been commercialised and promoted as beneficial. We have therefore explored how stem cells are represented to consumers online by DTC businesses, especially the underlying epistemic frames and how they fit within the current landscape of science, medicine, and consumer culture.Our analysis of the digitally mediated experimental stem cell therapy market in the UK shows that the boundaries around and between science and consumer culture are being re-configured. This is happening via the blurring of conventionally separate medical specialisations, distinctions between medical and cosmetics therapies and conventional and alternative medicine as well as between science, science fiction, and mythology. The epistemological and interpretative framework of regeneration and rejuvenation shifts the emphasis and causal chain of medical practice from sub-specialities and identifying aetiologies towards the single umbrella of regenerative or rejuvenation therapy. The uses of the notion of reversal in turn intertwine medical(ised) models of ageing with the demands of youth-centred commercial beauty culture.et al., et al., et al., These frameworks for conceptualising stem cell therapies are central to how their potential is represented and marketed to consumers. They are embedded within the emergence of biomedical lifestyle products that are ambiguously situated in relation to medical and consumer goods  are increasingly agentic in interpreting and prioritising the value of competing epistemic models and therapy options. To gain people’s attention and trust, conventional service providers must compete with commercial businesses offering alternative options and ways to imagine the present and future of stem cell medicine.The DTC stem cell therapy market exemplifies broader shifts in how commercial businesses and consumers are changing medical practices and re-drawing the boundaries of medicine itself via market logics and digital agency. The discursive and epistemic frames that businesses use build on and commercially harness broader cultural ideas and aspirations to construct powerful, appealing visions of what (regenerative) science could be(come). They promise something new and better to for health consumer to invest in.It is consequently not sufficient to presume the value of evidence-based biomedicine in delineating what the problem around experimental stem cell therapies actually is. Indeed, how we delineate and frame the problem shapes the kinds of responses that are developed to address it. We must also look beyond issues of safety, efficacy, etc. towards the digitally mediated discursive and epistemic contexts in which these therapies have proliferated to understand and appropriately respond to them. As Marres , p. 441