The deployment of structures that enable localized release of bioactive molecules can result in more efficacious treatment of disease and better integration of implantable bionic devices. The strategic design of a biopolymeric coating can be used to engineer the optimal release profile depending on the task at hand. As illustrative examples, here advances in delivery of drugs from bone, brain, ocular, and cardiovascular implants are reviewed. These areas are focused to highlight that both hard and soft tissue implants can benefit from controlled localized delivery. The composition of biopolymers used to achieve appropriate delivery to the selected tissue types, and their corresponding outcomes are brought to the fore. To conclude, key factors in designing drug‐loaded biopolymeric coatings for biomedical implants are highlighted. Strategic design of a biopolymeric coating can be used to engineer the optimal release profile of the therapeutics depending on the task at hand. Here advances in delivery of therapeutics from bone, brain, ocular, and cardiovascular implants are reviewed. However, after insertion, biomedical implants impose a set of ensuing problems which can jeopardize their performance. For instance, peri‐implant infections associated with orthopedic operations has been reported to be as high as 56% among patients. These procedures can also induce acute inflammatory responses that can eventually lead to fibrosis or fibrous encapsulation around them, which compromises the efficiency of the device and leads to device failure. Similarly, loosening of joint prosthetics has been associated with macrophage responses to implant debris particles, inducing release of proinflammatory cytokines that stimulates osteoclastogenesis and ensuing excessive bone resorption. Glial scar formation and low neuronal density in the vicinity of chronically implanted neural electrodes have also been correlated with implant‐induced inflammatory response.Loss of tissue function due to degenerative diseases and trauma compromises quality of life. This is most critical in cases where the inflicted damage is beyond the natural healing ability of the tissue, requiring biomedical implant insertion to extend the functional lifetime of the injured tissue.1 Thes encourage tissue integration and prolong implant life‐time. The local release approach also addresses limitations associated with systemic administration of therapeutics . Such promising observations have propelled the medical device community to merge various therapeutics with implantable devices. From the development of the first subcutaneous drug‐eluting implant in the 1930s, biomedical implants have had tremendous success in prolonging drug administration in a precise and efficient manner , allowing them to mimic the physical properties of different tissues in the human body. Control over the crosslinking density of the polymeric networks can also be used to fine tune the release profile of embedded therapeutics. Polymeric coatings are typically applied to the surface of the implants using techniques including but not limited to dip‐coating, electrospinning, layer‐by‐layer self‐assembly, and surface grafting, with/without catechol mediating layer, and electrochemical deposition. Release of therapeutics from polymeric coatings can occur passively by diffusion, or actively in response to environmental triggers  or external stimuli   Figure . Given tResponsive biopolymers can sense specific signals in the operational environment or biological processes to then trigger release of therapeutics. Responsive release modalities provide a unique opportunity to time the therapeutic administration commensurate with the biological events that ensue implant insertion. This is particularly important in providing short‐ and long‐term protection against peri‐implant infection by using particular trigger events that are ensuing the infection initiation.42 This paper reviews advances in delivery of therapeutics from bone, cardiovascular, ocular, and neural implants. We have focused on these areas to highlight that both hard and soft tissue implants can benefit from controlled localized delivery. We have reviewed the biopolymeric coating systems used to facilitate therapeutics delivery from these implants, with a special focus on the chemistry of biopolymers and techniques that were used to encapsulate the therapeutics. Lastly, future trends in development of drug‐eluting biomedical implants are highlighted.Generally, controlled release of therapeutics from medical implants has been employed to bring about one or more of the following: i) to facilitate implant integration, ii) to control host tissue inflammation, and/or iii) to prevent implant associated infections.33 Thi2 However, in certain cases including traumatic injuries, cancer, and osteoporosis, full recovery of bone structure and function are hampered leading to debilitating effects. To this end, clinical methods such as autografts and allografts have been used as gold standards to treating bone diseases, yet these approaches are often associated with issues such as disease transmission, limited autologous resources, and rejection of allograft tissue. Alternatively, the use of bone implants overcomes the above issues and can also provide mechanical support allowing functional recovery.Bone tissue, unlike many others in the human body, is capable of self‐healing and being structurally integrated with surrounding undamaged counterparts, without production of any fibrotic scars.43 HowBone implants can be categorized into nonload bearing and load bearing implants, and correspondingly a wide range of materials have been used to manufacture them; including metallic alloys (such as titanium or magnesium), ceramics , and polymers .46 Titanium‐based bone implants have been widely used in clinical applications either as permanent prostheses, or as temporary implants. Nevertheless, titanium implants are prone to issues such as bacterial infection and weak osseointegration that could jeopardize their long‐term clinical application. To address these, therapeutic‐eluting bone implants have been developed  are required to enhance the adhesion of the coating to the substrate.Titanium and its alloys are low density materials that possess high strength and resistance to corrosion, and on account of such properties they have been used frequently to manufacture medical implants.47 TitIn the polymeric coating systems, the therapeutics are either: i) physically entrapped within the polymer matrix, or ii) they are anchored onto the polymeric chains via chemical linkages. polymer‐drug affinity, concentration, crosslinking density, degradation rate, and swelling behavior. These systems have been used to endow release of therapeutics from bone implants, mainly due to their simplicity and easy chemistries.The release of therapeutics that are physically entrapped within the polymer coating is often passive, and the release rate is determined by polymer properties such as surface charge,57 pold,l‐lactide) for local delivery of growth factors (GFs), namely insulin‐like GF‐I (IGF‐I) and transforming GF‐beta 1 (TGF‐β1). After 42 days of osteotomy, the GF‐treated rat group showed an enhanced biomechanical stability and a significantly higher callus density  when compared to the uncoated group. This study also emphasized the importance of the manner that GFs are delivered in‐situ, since the direct release of GFs into the medullary canal demonstrated a higher bone healing than the extramedullary GFs release. This homopolymer does not allow tuning of the therapeutic release profile, however block copolymers containing multiple repeating units can be implemented to endow some level of control over passive delivery of therapeutics. As an alternative approach, the LbL self‐assembly technique allows a homogenous surface coating of implants with control over thickness. For example, a novel drug release system was developed on the basis of LbL deposition of poly(acrylic acid) (PAA) and poly‐l‐lysine (PLL) coatings on titanium. Titanium discs were first plasma etched in argon, and subsequently subjected to alternating PAA and PLL solutions. Penetration of an antibiotic  into the coating was achieved by placing droplets of TC solution on top of the coating at 37 °C for 4 days. In vitro results showed that the implants were capable of releasing TC over a period of 15 days in both neutral (pH = 7.4) and acidic (pH = 4.5) conditions. The pH‐dependent 2‐fold increase in TC release from titanium implants observed at pH = 4.5 was attributed to changes in the degree of ionization of the polyelectrolytes, which completely eradicates Porphyromonas gingivalis bacterial colonies in vitro. LbL self‐assembled coatings provide a platform for pH‐sensitive release of therapeutics, mainly due to the interaction of oppositely charged polymers that form ionically crosslinked polyelectrolyte coating complexes. To further reinforce this network structure, crosslinking agents can be incorporated into the polyelectrolyte complex coatings. For example, Ti–6Al–4 V alloy scaffolds were subjected to LbL assembly using PLL as a polycation and hyaluronic acid as a polyanion. These polyelectrolyte multilayer coatings were then crosslinked using different amounts of 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide (EDC), and subsequently incubated with bone morphogenetic protein 2 (BMP‐2) . The initial burst release of BMP‐2 was inhibited by increasing the EDC crosslinker concentration in the multilayer films . A rat ectopic model showed that the use of the crosslinked coatings resulted in better osteoinductive performance than scaffolds containing adsorbed BMP‐2 .Titanium plates have been coated with biodegradable poly((TGF‐β1).64 Afts Figure 2. A rat2 Figure 3. For instance, β‐cyclodextrin has been grafted onto a chitosan backbone (Chi‐CD) and coated on Ti6Al7Nb substrate via LbL self‐assembly to control the release of 1,25‐dihydroxy‐vitamin D3 (VD3) and calcitonin . The coated implants showed a sustained release of therapeutic agents over a period of 14 days, which upregulates the expression of calcium‐binding proteins and BMP2 and then stimulates in vitro calcium deposition and cell differentiation. Given the essential role of macrophages in repairing bone tissue, the response of RAW264.7 cells (a murine macrophage cell line) to coated implants was evaluated, which showed that these implants could suppress the secretion of osteoclastogenesis‐related cytokines. The in vivo testing of VD3/CT coloaded implant in osteoporotic conditions showed remarkable enhanced osseointegration and the highest interfacial binding strength. Another approach used to modify the burst release of therapeutics is the incorporation of the therapeutical agents in nanoparticles and their further loading into the polyelectrolytes complexes. For example, gold nanoparticles were decorated with siRNA molecules targeting Cathepsin K  and then assembled onto a titanium implant by LbL deposition of chitosan and gelatin polyelectrolytes . This system enabled sustained release of siRNA nanovectors over a period of 8 days when tested in vitro. When cultured with RAW264.7 cells, they reduced the expression of CTSK mRNA and caused macrophage‐induced synergy in up‐regulation of at least seven bone and vascular growth factors. Insertion of these implants in an osteoporosis rat model significantly enhanced osseointegration effects  with improved angiogenesis of blood vessels associated with the regenerated bone.The burst release of therapeutics from polyelectrolyte complexes can be reduced by the incorporation of molecules that have an affinity toward the bioactive ingredient.73 Fors Figure 1.[71s Figure 2 with i or stimuli‐responsive release can be achieved. The immobilization of therapeutics can be a useful approach in cases where long‐term therapeutic effects are expected from the implant. On the other hand, stimuli‐responsive release is ideal in scenarios where drugs need to be delivered at specific time points and follow a certain pattern of release to fulfil their optimal therapeutic effect. Permanent immobilization of therapeutics onto the polymer coatings are achieved using chemistries such as Michael addition, Schiff base reaction, epoxide ring‐opening reaction, click chemistry, and radical initiated reaction.The therapeutics agents can also be anchored onto the polymer coating through chemical linkers that can anchor therapeutic agents on the implant surface. Depending on the type of chemical linkage between the therapeutic and the polymer, either permanent immobilization77 or  Then, the polymer brushes have been further functionalized with low‐molecular‐weight quaternized polyethyleneimine and alendronate, an antibacterial and antiosteoporosis agent, respectively. Biomedical device‐associated infections animal model indicated that implants inhibited bacterial infection and provided a supportive environment for bone‐implant osseointegration leading to high biomechanical stability of implants. In other work, a titanium implant was coated with polydopamine to facilitate conjugation of the antibiotic cefotaxime sodium (CS) onto the surface of the implant. The immobilization of drug on the polydopamine coating was achieved via Michael addition and Schiff‐base reactions between the amino groups in CS and the catechol/quinone groups in polydopamine. In vitro results showed that the antibiotic‐grafted titanium effectively prevented adhesion and proliferation of two different bacteria. Despite the success of permanently immobilized therapeutics on the polymer coating, the therapeutic effect of these systems is restricted to the immediate surface of the implant. Consequently, stimuli‐responsive chemical linkages such as peptide bonds that are sensitive to bacterial enzymatic activity have emerged as a useful strategy to induce the release of therapeutics upon infection. Vancomycin (a glycopeptide antibiotic) has been covalently attached to poly(ethylene glycol) dimethacrylate hydrogel coatings using a nuclease sensitive oligonucleotide linker, to endow sensitivity to S. aureus micrococcal nuclease . The insertion of these coated titanium pins into mouse femoral canal inoculated with S. aureus resulted in complete eradication of the bacteria from both the implant surface and its periprosthetic bony tissue environment, preventing osteolysis in the surrounding tissue .Ethanediamine‐functionalized poly(glycidyl methacrylate) (PGED) brushes have been grafted onto titanium implants using surface‐initiated atom transfer radical polymerization.76 Thee Figure 1.[72e Figure 2. Also, the polymer degradation rate must be adjusted carefully to allow attachment of newly formed bone to the surface of the implant, ensuring complete osseointegration. Application of functional nanoparticle‐loaded polymeric coatings on bone implants has recently gained a lot of attention. Owing to peculiar properties of these nanoparticles they can either be used for delivery of specific genes to facilitate osseointegration, or they can endow photothermal and photodynamic properties to the implants to prevent periimplant infections. A summary of therapeutic‐releasing biopolymeric coatings on bone implants is provided in Table Therapeutic‐loaded polymeric coatings provide a unique opportunity to provide control over the release profile, due to the diverse chemistries that can be engineered to endow specific spatiotemporal release patterns. However, factors such as polymer degradation products could potentially induce negative immune‐system responses, which could be detrimental to the performance of the implant. For instance, polylactic acid degradation generates acidic products (lactic and glycolic acids) that lowers the pH, and this, in turn, negatively affects the cytokine profiles of inflammatory cells adjacent to the implants.87 Als3 Consequently, neurological complications caused by injury or disease is detrimental to an individual's quality of life by compromising their normal daily activity. Such neurological complications could lead to loss of hearing, vision, compromised memory, and paralysis. These neurological complications are associated with loss of neural function, which is worsened given that neurons are usually incapable of regeneration. Normally, some of the neural pathways upstream of the defective site remain functionally intact, and they can be explored via neural implants to restore lost function. For example, implantable‐device technologies capable of transferring electrical and chemical signals to and from the nervous system have generated possibilities to ameliorate dysfunction resulting from disease or injury. Such implantable devices include auditory brainstem implants; deep brain stimulators; and intracortical microelectrodes. However, insertion of these devices in brain tissue is often associated with local injury and a progressive inflammatory tissue response, which can interfere with electrophysiological signals, compromising the device function.Brain is the most complex tissue in the human body, and it is responsible for almost every physiological action in the body.95 ConFigure  These devices normally contain electrode arrays that are insulated with soft and flexible polymeric materials to make them more compatible with the curved and easily‐damaged surface of the brain. Polydimethylsiloxanes (PDMS) and polyimides (PI) are two of the most prevalently used insulating polymers, mainly due to their favorable features such as flexibility, chemical and radiation inertness, durability, and good biocompatibility.To address this hurdle, controlled delivery of therapeutics from neurobionic devices has been shown to provide promising results Figure 5.[103 or via polymeric coatings on top of these. The insulating polymer can only afford passive release of therapeutics without any control over the release rate. On the other hand, polymer coating can provide a degree of versatility to tune the release profile either in a passive or active manner.The local release of neurotrophins and/or anti‐inflammatory drugs from these devices is achieved either through release from the insulating polymer111 orl‐lactic acid (PLLA) or poly(lactide‐co‐glycolic acid) (PLGA) nanofibers loaded with dexamethasone. Next, PEG was patterned on the nanofibers as a drug release facilitator, on top of which a conductive layer of poly‐poly(styrenesulfonate) (PEDOT:PSS) was polymerized to counter the loss of electrical properties caused by PEG patterning. In vitro drug release experiments showed that implants coated with PLGA nanofibers had a faster release compared to that from PLLA fibers (due to the difference in their degree of hydrophilicity), and the addition of PEG further increased the release rate. Moreover, electrodes coated with PEDOT:PSS had a lower impedance (342 Ω mm2) when compared to PEG‐patterned electrodes (1046 Ω mm2). In addition, testing of these nerve cuff electrodes in an ex vivo SD rat's sciatic nerve showed successful recording of the nerve's signals. However, in vivo evidence was lacking from this work to truly evaluate the effect of the released drug. Consequently, the same group coated a nerve cuff electrode with a PEG hydrogel embedded with PLGA microspheres (MS) containing cyclosporin A  . Subsequently PEDOT:PSS was deposited on the four‐line electrodes site on the hybrid hydrogel‐coated cuff electrode to improve the electrode‐nerve tissue interface. Accordingly, these electrodes allowed controlled release of cyclosporin A over a period of 40 days when tested in vitro. Also, it was shown that PEDOT deposition can reduce the impedance of platinum electrodes. In vivo testing of the PEDOT:PSS coated electrode with PEG hydrogel and cyclosporin A containing microspheres significantly reduced fibrous tissue deposition  and increased axonal density . Moreover, histological analysis of sciatic nerves treated with coated implants containing cyclosporin A revealed a more highly packed nerve fiber as well as myelin sheath in comparison with that in control and hydrogel + PEDOT treated groups.In brain/neural implants, biopolymer coatings are the sole candidate for drug delivery, mainly due to the soft and delicate nature of the tissue that necessitates the use of soft materials to avoid physical damage. Specifically, given the essential role of electrical signals in the performance of brain implants, electrically conducting polymer coatings have emerged as an alternative to facilitate drug release. For example, polyimide‐based nerve cuff electrode was coated with poly‐ethasone.113 Nen Figure 2 and iny Figure 3. Moreo and external stimuli provides a further dimension. To avoid the electrode insertion trauma (EIT), silicon‐based electrode arrays were dip‐coated with a PEG‐maleimide hydrogel that contained an Interleukin‐1 receptor antagonist  and subsequently crosslinked using a peptide linker . In fact, the peptide crosslinkers were protease‐sensitive, which allowed the release of IL‐1Ra in response to upregulated proteases during inflammation. First, hydrogels were placed in conditioned media from cells stimulated with lipopolysaccharide (LPS) (to induce secretion of inflammatory proteases) or normal media. Faster release of IL‐1Ra was observed overtime under simulated cell culture conditions . Subsequently, in vitro testing showed that these implants significantly reduced attachment of glial cells and attenuated inflammatory cytokine release, while facilitating increased release of IL‐1Ra over time in response to inflammatory cytokines. However, in vivo experiments only showed minor improvements in inflammatory cell markers, albeit neuronal survival was significantly higher for coated electrodes .The cases that were discussed so far allowed sustained release of drugs from brain implants in a passive manner, yet active delivery in response to both internal115 anr Figure 1.[115s Figure 2. Subses Figure 3. To this end, electrically conducting polypyrrole/para‐toluene sulfonate (PPy/pTS) containing neurotrophin‐3  was electrochemically deposited onto cochlear implant electrodes for preventing gradual degeneration of spiral ganglion neurons (SGNs). The in vitro results revealed that the amount of released NT3 can be tuned by using a biphasic electrical stimulation. Of interest, implanting PPy/pTS/NT3 electrode arrays in the cochleae of guinea pigs followed by electrical simulation caused higher SGN densities in implanted cochleae when compared to that in animals implanted with PPy/pTS‐coated electrodes.Electrically conductive polymers present a useful coating option for brain implants, as they facilitate large drug loading capacity as well as electrical stimulation.118 Toco‐4‐methacryloyloxy benzophenone‐co‐4‐styrenesulfonate) hydrogel and PEDOT coated on an electrode, provided large loading capacity of dexamethasone and actively released the drug in response to electrical signals. These electrodes allowed on‐demand delivery of dexamethasone over a period of 12 weeks in fully awake animals using a cyclic potential waveform. Drug‐functionalized probes showed uninterrupted performance over the entire chronic study. Of importance, histological evaluation of the tissue surrounding the probe showed that electrodes exposed to on‐demand drug release had neurons closer to the electrode sites compared to controls. A summary of therapeutic‐releasing biopolymeric coatings on brain implants is provided in Table Lastly, a mixture of poly is necessary which has given rise to fluctuations in drug concentration over the ocular structures. To amend this, ocular lenses  were suggested as a platform to allow local and sustained release of therapeutics to the eye. This will enhance the ocular absorption and consequently avoid the possible negative side effects of the drugs associated with multiple administrations.The eye is divided into two main anatomical regions: the anterior and posterior segments. Various diseases  can harm regions in both anterior and posterior segments of the eye.124 Th Control of drug release from contact lenses is essential, ensuring adequate concentration in the eye to yield optimal therapeutic effect over the treatment period. Compared to drug‐soaked lenses , that are prone to burst release and low drug loading capacity, emerging ocular lenses made from techniques such as vitamin E barriers, molecular imprinting, micro‐ and nanoparticles laden, inner layer‐embedded lenses can facilitate the maintenance of local dosage (within a therapeutic window) for a longer period of time. Despite such achievements, premature release during manufacturing and storage have hindered the potential application of drug eluting ocular lenses in clinical use. Moreover, timely mannered drug dosage adjustment is imperative as the disease/condition is progressing. However, the common theme among drug‐eluting ocular lenses is release at a predetermined rate which is not compatible with the changing physiological conditions of the disease.Depending on the material used for preparation, ocular lenses can be classified as hard or soft. Generally hard lenses are made up of rigid polymers such as polymethyl methacrylate (PMMA), whilst soft lenses are made from soft and flexible polymers such as poly (2‐hydroxyethyl methacrylate) (pHEMA)‐based hydrogel or silicone hydrogel.126 CoFigure  or spin‐coating, or through LbL deposition of biopolymeric layers.Consequently, biopolymer coatings were applied onto the surface of lenses to inhibit premature drug elution and assist in providing on‐demand release of therapeutics Figure 7. The c This is the main ensuing condition after IOL implantation in cataract surgery, because of residual lens epithelial cells (LECs) proliferation in the lens capsule. Given the transmittance requirements of the intraocular lens, concentric annular coating with a thin center and thick periphery was obtained. In vitro drug release profiles obtained from these systems showed a four‐phase pattern that contained an initial burst release for the first week, followed by a linear release from week 2 to 9, with an ensuing secondary burst release from week 9 to 12, and ending with a plateaued release from week 12 to 16. The initial burst release had an inverse correlation with the PLGA concentration. The use of a PLGA coating only slightly decreased light transmittance of the pristine IOLs (from 87% to 83%), showing no major impact on the optical properties of IOLs. The in vitro results showed that modified IOLs were capable of inhibiting LECs proliferation and induced cell death. After two weeks of implantation in rabbit eyes, unmodified IOL showed excessive fibrosis of residual cells in the vicinity of the implant. In contrast, no posterior capsular opacification was detected in the CsA‐loaded PLGA coating‐modified IOL‐implanted animals. The results suggested that CsA‐loaded PLGA coating on the surface of IOLs was effective in the prevention of posterior capsular opacification.A concentric ring‐patterned cyclosporin A (CsA)‐loaded PLGA was spin‐coated onto the surface of an intraocular lens (IOL) to effectively prevent posterior capsular opacification.148 ThFigure 1). The coating layers consisted of a polyanionic copolymer of acrylic acid and 1‐adamantan‐1‐ylmethyl acrylate (P(AA‐co‐AdA)) and a polycationic poly(ethyleneimine) (PEI). Next, host–guest interactions between β‐cyclodextrin−levofloxacin (β‐CD‐LEV) and AdA were used to develop an antibacterial coating on the CLs. These implants were designed to be reusable by simply removing the adherent dead bacteria using sodium dodecyl sulfate (SDS) and reloading them with the drug by simply immersing them in β‐ CD‐LEV. By tuning the number of bilayers, one could control the drug loading capacity as well as coating thickness. In vitro  and in vivo  experiments revealed the antibacterial and germicidal efficacy of the coatings.Bacterial keratitis is a serious ophthalmic condition that can lead to severe visual impairment. In a recently published work, a combination of LBL self‐assembly and host–guest interactions was utilized to coat the surface of corneal contact lenses (CLs) with the aim of enhancing bioavailability of the drug for effective treatment of bacterial keratitis Figure 8A1.[11). The copolymer containing coumarin moiety was a poly (polyethylene glycol methacrylate‐co‐glycidyl methacrylate‐co‐Coumarin methacrylate) which was attached onto the IOL surface. 5‐FU can be attached or released from the copolymer under the action of UV radiation at 365 or 254 nm, respectively. In vitro results showed that coated IOLs succeeded in preventing LEC adhesion and proliferation via irradiation . The on‐demand release upon irradiation was a function of UV light intensity and radiation time. In vivo observations revealed that surface‐modified IOLs were capable of reducing the occurrence of posterior capsular opacification after light radiation with minimal side effects .Recently, photo‐ and pH‐responsive coatings deposited on the surface of CLs have been used to facilitate on‐demand drug release. The photoresponsive coating on the surface of IOLs was developed based on reversible photodimerization and photolysis of coumarin and 5‐FU Figure 1.[155n Figure 2. The os Figure 3. The dynamic covalent bonds between hydroxyls of vancomycin and phenylboronic acid (PCVB) were used to facilitate drug loading. These interactions possessed sensitivity toward acidic pH that can be generated because of bacterial infection. Concentration of the monomer and duration of SI‐RAFT polymerization determine the thickness of the coating as well as the loading capacity of the drug. Furthermore, in vitro and in vivo assessment of the PCVB coating yielded improved antibacterial and anti‐inflammatory effects. The results of this study demonstrated that the tissue environment associated with bacterial infection can be used as a trigger to allow responsive release of therapeutics, representing a potential solution for bacterial keratitis.Along similar lines, a pH‐responsive coating was obtained via surface‐initiated reversible addition–fragmentation chain transfer polymerization (SI‐RAFT) of phenylboronic acid monomers  into uniform brushes.156 ThTable Drug release patterns must be consistently optimized in response to disease progression, treatment response, and other concurrently occurring conditions. In these cases, polymer coatings with active release mechanisms could be useful. Amongst external stimuli, light represents a promising trigger to initiate/control drug release, mainly because it can be easily applied remotely with high spatiotemporal precision. In this context, ultraviolet (UV) radiation can modulate the release profile of therapeutics by means of either photocleavage, photoisomerization, or photo‐crosslinking. At the same time, reloadable polymeric coatings on contact lenses provide another useful feature for longer‐term treatments. As a result, multimodal polymer coatings such as the ones with responsive release and reloadable attributes hold a great potential for improving ocular delivery of therapeutics. A summary of therapeutic‐releasing biopolymeric coatings on ocular implants is provided in 5 Due to the significant morbidity and mortality due to CVDs, different medical interventions have emerged to improve treatment efficacy. Cardiovascular stents have been used as an important and versatile method to address coronary and peripheral artery diseases. However, stents are bioinert metallic devices and their implantation can lead to inflammation, restenosis, and thrombosis. To reduce such side‐effects, bioactive compounds such as vascular endothelial growth factor (VEGF) to support neovascularization, rapamycin and paclitaxel to suppress foreign body reactions, and heparin to prevent blood clotting, have been incorporated into stents usually with the aid of a biodegradable polymer as a coating  that are often used produce acidic degradation products, leading to local inflammation and delayed tissue healing due to the local acidification. Hence, naturally derived biopolymers such as zein protein (from corn) or alginate (from seaweed), that develop less inflammation in long‐term applications, have been used to substitute synthetic biodegradable polymers.Cardiovascular diseases (CVDs) are one of the most prevalent chronic diseases and the leading cause of death worldwide.159 Du LbL self‐assembly, and drug‐loaded nanoparticles immobilized on/in the coated polymeric matrix have been utilized.To further modulate release of the drugs and achieve a sustained release profile, multilayer polymer coatings,166 Lb To overcome this issue, a proliferation‐induced drug release was reported by Gliesche et al. They developed a biodegradable poly‐l‐lactic acid (PLLA) stent where model drugs are covalently conjugated to the surface by cleavable peptide linkers . They demonstrated that the peptide linker can be cleaved, and the model compound fluorescein can be selectively released by matrix metalloproteinase‐9 (MMP‐9) secretion. MMP‐9 is secreted in human coronary artery smooth muscle cells (HCASMC) proliferation and not proliferating human coronary artery endothelial cells (HCAEC) . Fluorescein release was observed only in the presence of proliferating HCASMC . Although these findings suggest a promising method for selective release of drugs, further studies need to be performed to prove the safety and efficacy of this method in vivo.Although drug‐eluting stents are successful in reducing the risk of restenosis compared to bare metal stents, they still have some drawbacks such as stent thrombosis due to inhibition of endothelialization and the need for prolonged antiplatelet therapy for patients after stent implantation.168 To) Figure 2. FluorC Figure 3. Altho Hydrogen sulfide is a signaling molecule that plays a vital role in maintaining cerebral vascular homeostasis, protecting, and regulating the central nervous system, promoting angiogenesis and anti‐inflammatory mediators. It can also be utilized in vascular remodeling and regulating the vascular inflammatory response. Hydrogen sulfide, however, is cytotoxic at high dosages, has a short lifetime, and cannot be directly administered. To embed the ACS14 into a pH‐responsive coating, first the surface of stainless‐steel stents was modified with dopamine. Next, the pH‐responsive coating was made layer‐by‐layer using catechol‐modified chitosan and catechol‐modified hyaluronic acid. This polymeric coating displayed increased swelling in response to the acid microenvironment of the implantation lesion. As a result, the coating was able to regulate the release of the ACS14 according to the microenvironment of the stent with a pH‐dependent release profile. In vitro studies showed that platelet adhesion and activation as well as fibrinogen adsorption and denaturation can be inhibited using this drug‐loaded coating. Proliferation of smooth muscle cells and macrophages were also inhibited, reducing the inflammatory response at the interventional site as well as promoting the formation of new blood vessels.Another method used to achieve controlled release was the use of a pH‐responsive matrix filled with the drug. Since the angioplasty site shows inflammation which creates a slightly acidic microenvironment compared to normal tissue, Lu et al. introduced an unorthodox strategy for the treatment of cardiovascular disease. They developed a pH‐responsive coating on a stent loaded with Hydrogen sulfide donor (ACS14) as an intelligent drug release system adjusted specifically to the acidic and inflammatory environment of the intervention.164 Hy In a similar approach, a smart coating was developed on the surface of a cardiovascular stent that can release therapeutics in response to oxidative stress (at vascular lesion sites) . The coating layer was composed of a mixture of epigallocatechin gallate (EGCG) and cysteine hydrochloride, which were loaded with pitavastatin calcium. EGCG and pitavastatin calcium provided concurrent antioxidant activity and inhibition of smooth muscle cell proliferation. Specifically, smart release of drug in response to reactive oxygen species was provided via breaking of disulfide bonds of cystamine. The rate of drug release had a direct correlation with the degree of oxidative stress. In vitro observations showed that the coating possessed favorable properties such as promotion of endothelial cell proliferation and migration, in conjunction with inhibition of SMC proliferation. Moreover, animal experiments proved the biosafety of the coatings and the ability to concomitantly promote endothelialization while inhibiting neointimal hyperplasia after stent implantation  Figure 1.[172n Figure 2,B3. ThDrug eluting stents for local release of drugs at the lesion site have revolutionized the field of interventional therapies. Particularly, controlled drug release in response to conditions of the lesion microenvironment are of much interest in personalized treatments. Along these lines, enzyme‐ and pH‐sensitive polymer coatings were employed to facilitate smart‐release of therapeutics in response to diseased tissue microenvironments. Another approach to instigate on‐demand release of therapeutics is the use of externally applied signals in the form of ultrasonic or magnetic pulses. This allows for drug presentation at the ideal time and at the ideal dosage needed for a specific condition in a particular patient.174Table A summary of therapeutic‐releasing biopolymeric coatings on cardiovascular implants is provided in 6 The selection of the biopolymer is based on the difficult balance of all these properties. For example, for some bone implants, biomaterials should resist deformation and should be able to support heavy loads. However, at the same time, the same material must be flexible, to avoid cracking when exposed to tension, as well as light to enable motion. For neural microelectrode implants, the biomaterial coating or sheathing should encourage neurite outgrowth toward the surface of the electrode, while avoiding the recruitment of glial cells and fibroblasts which can lead to glial scarring, compromising activity. The microelectrodes of neural implants must also maintain electrochemical and physical stability in an adverse tissue environment to sustain the efficacy of the device for several years. Coatings for implants for heart and coronaries must demonstrate exceptional biocompatibility with blood and enable blood flow optimization. This will prevent hemodynamic adverse responses, including thrombogenesis, which could lead to implant rejection and potentially lead to death. For ocular release, the biomechanical and optical properties of the implants should also guarantee they do not affect the vision or restrict oxygen permeability, ensuring biocompatibility. The implants should also have a moist surface and adequate flexibility to prevent tissue irritation. Another consideration is that tissue‐type can determine the nature of the stimuli that can be used to stimulate active‐release of therapeutics. Electrical pulses have been used to initiate release of therapeutics from brain implants, whereas photoradiation was used to allow on‐demand release in ocular implants. Biological changes in diseased tissue microenvironment can also be used as stimuli to initiate the release of therapeutics. For instance, enzymes and pH changes associated with infections have commonly been used as triggers to facilitate release from bone, brain, ocular, and cardiovascular implants.In this work we have reviewed the most recent advances in the field of drug‐eluting implants, for both hard‐ (bone) and soft‐tissues . Coating of implants with drug‐loaded multifunctional biopolymers allows precise control over local release of therapeutics, which subsequently leads to enhanced implant performance and better integration within the host tissue. However, the selection of biopolymeric coating can be an intricate task. The coating must provide a surface that mimics the physicochemical properties of the host tissue to promote the integration of the implant and also provide an environment that allows for high drug loading capacity and the desired drug delivery profile over time.176 Th Targeting moieties can be added onto these nanogels to specifically target certain cell‐types within the tissue. Furthermore, theranostic nanogels  can be used for simultaneous diagnosis and treatment. Another emerging area of research within biopolymeric coating of implants is the application of antimicrobial polypeptides in combination with antibiotics. Most bacteria can inhibit the action of antibiotics by limiting their intracellular accumulation, hence membrane‐active antibacterial polypeptides can be used as an encapsulating matrix to achieve synergistic effects.The future direction of delivery from medical implants will be determined by the development of new biopolymeric entities. Given the importance of cellular penetration of therapeutics, nanogels capable of breaking down into nanoparticles are an ideal candidate for surface coating implants.184 TaBiopolymers sensitive to both internal and external stimuli have been successfully used to allow on‐demand release of therapeutics. However, for successful transition of these biopolymeric coatings to clinical applications, they must comply with multiple conditions. They should be nontoxic and not act as an irritant when implanted. Second, the biopolymers degradation profile must be tuned to the specific application in order to persist in the implanted location for as long as necessary, but slowly degrade into safe subunits when no longer needed. Third, the biopolymeric coating should be easy to apply and ideally would be readily refillable for repeating administration. Fourth, the cost associated with synthesis and coating of biopolymers should be taken into consideration, as bench‐to‐bedside transition could be an exhaustive and expensive process. Last obstacle is the acceptance by industry and regulatory bodies, as often these innovations do not have a well‐established preclinical testing modality nor any specific classification to obtain their approval.The market for therapeutic‐releasing biomedical implants is one that is growing. The advantages that this delivery route presents over more traditional therapeutic delivery modalities, such as oral tablets, make it likely that this biotechnology will continue to grow and that the number of biomedical implants on the market will increase. Some of the advantages of these implants are: patient compliance, stability of drugs within these devices, enhanced integration in the tissue, and longer lifetime. Overall, local delivery of therapeutics from medical implants is a promising approach that provides performance enhancement, leading to significant improvements in the patient's quality of life.J.C. is a co‐founder and shareholder of TargTex S.A. Targeted Therapeutics for Glioblastoma Multiforme. All other authors declare no conflict of interest.


Acipenser fulvescens) in the well‐studied population in Black Lake, Michigan, USA. Spawning lake sturgeon  and larvae (N = 3436) were genotyped during each of seven consecutive years (2001–2007). Factors associated with individual reproductive success differed between sexes and varied among spawning groups within a year and among years depending on spawning date  and spawning locations . Female reproductive success increased nonlinearly with increasing body size. Male reproductive success increased with increasing residence time in spawning areas and, to a modest degree, with increasing body size in a nonlinear fashion. Fixed effects of repeatability in spawn timing and location across years led to consistently higher or lower reproductive success for females. Results identified factors, including time spent at spawning areas by males and intersexual encounters and mate number, that contributed to higher interindividual variance in reproductive success and affected population levels of recruitment, the degree of subpopulation genetic structure (lack of isolation by time), and effective population size.Quantifying effects of individual attributes and population demographic characteristics that affect inter‐ and intrasexual interactions and adult reproductive success, and the spatial and temporal contexts in which they are expressed is important to effective species management. Multi‐year individual‐based analyses using genetically determined parentage allowed the examination of variables associated with the reproductive success of male and female lake sturgeon  and apportion variation RS into biotic and environmental factors using a novel mixed model analysis. Fixed effects of repeatability in spawn timing and location across years led to consistently higher or low RS at the individual level for males and females. Results identify the importance of factors, including male mating behavior associated with intersexual encounters and mate number, that contributed to interindividual variance in RS and population levels of recruitment, the degree of subpopulation genetic structure (lack of isolation by time), and effective population size. Using parentage analysis based on microsatellite genotypes of adults and offspring over a 7‐year period 2001–2007), we quantified the number of offspring produced (reproductive success) for each adult during one or more years that individuals were captured while spawning. We developed novel mixed effects analyses to account for uneven sampling among years and different interbreeding intervals among individuals. Multi‐year individual‐based analyses, in which the same individuals were captured and recaptured across several years, allowed us to quantify the degree of inter‐ and intraannual variability in the effects of factors contributing to male and female reproductive success. Given the high degree of individual repeatability in male and female spawning date and location , the largest tributary to Black Lake, Michigan, USA  was collected for genetic analysis. All individuals were measured for weight (kg), fork length , and total length . Temporal variation in spawning date is widely observed in lake sturgeon , and for females, spawner abundance was set at 250 for years 1 and 2 of the simulation. Following some initial variability in annual abundance estimates, the abundance of males spawning each year stabilized at 629 or 62.9% of all males. At year 25 of the simulation the estimated abundance of females spawning each year was 274 or 27.4% of all females. These proportions were then used to estimate total spawner abundance for 2001–2007 by multiplying with the total population abundance of males and females from the Pledger et al.  from upstream spawning areas to the time of settlement in downstream areas of the river. The larval sampling protocol  between males and females /(max–min)), where X is the unscaled variate and min and max are the minimum and maximum of the X within a year. In models that included a given continuous standardized variable, both the original standardized value and its square were included as variables, thus allowing for a type of nonlinear relationship. We adopted this approach because preliminary analyses demonstrated that the full model that included quadratic terms substantially outperformed the otherwise fully saturated fixed effect model that did not .To place explanatory factors on the same scale and improve model estimation ability the continuous variables were rescaled so they ranged from a minimum value of 0 to a maximum value of 1 within each year  and because we assumed that relative values within a year would be most predictive of differences within a year. For females, we considered the following potential fixed effect explanatory variables: standardized body size /, where TL is unstandardized total length as a continuous factor, standardized days  after the start of the spawning season a female reproduced (Date) as a continuous factor, and reproductive zone , the correlation was still weak but stronger for unstandardized values . The spawning zone variable was dropped because single males often mated with females located in both upstream and downstream zones and not just with females located in the spawning zone they were first observed in .In the main analysis for males, we used standardized time on the spawning ground (residence time) instead of spawning date, and standardized body size was calculated as for females but using male lengths observed that year. The residence time was based on the difference between the last and first confirmed spawning date based on parentage analysis and the dates of spawning for females a male shared offspring with. In cases of a male having one mate, the residence time was the day difference between the capture date of the male and his mate. Only males with at least one offspring were included in the analysis. The residence time was used instead of a spawning date because males generally contributed offspring based on spawning with multiple females potentially over the entire spawning period rather than on a single date  or residence time , standardized body size, and reproductive zone , we evaluated the random effects to include in the model based on a model with all the fixed effects. Three random effects including year, individual observation each year (Obs), and individual fish  were evaluated as factors affecting the reproductive success of lake sturgeon females and males. For sex‐specific models containing all the fixed effects Table , the ran3.4AIC results for fixed effects were similar for the two random effect models considered Table , and est3.5As for females, two random effect models, one with all three random effects and one that excluded the individual effect, were plausible (within three AIC of the best model), but in the case of males, the lower AIC model had all three random effects. We focused on the evaluation of fixed effects for the random effects model that included all three variables, although model choice among fixed effects did not depend on the random effects models, and as for females estimated fixed effect parameters were similar regardless of the random effects model (results not shown).Reproductive success for males and females was skewed Figure . For mal4We quantified the variation in, and factors affecting male and female reproductive success for lake sturgeon, a long‐lived iteroparous fish of conservation concern over a period of 7 years constituting multiple reproductive events for much of the adult population  specifically . Context‐dependent male modification of behavior is commonly observed in a taxonomically diverse array of species, including fishes generally , what biological or physical stream conditions are associated with this behavioral plasticity? Based on visual inspection of data on the numbers of adults spawning each day of the season  include biotic factors, such as predation , for example, male–male competition occurs where dominant males who occupy the closest position to females can fertilize more eggs and, therefore, realize higher reproductive success than peripheral males  in the Kootenay River ; data curation (lead); formal analysis (supporting); methodology (supporting); validation (supporting); writing – original draft ; writing – review and editing . James Bence: Conceptualization (supporting); formal analysis (lead); investigation (supporting); methodology (supporting); validation (supporting); writing – original draft (supporting); writing – review and editing (supporting). Patrick S. Forsythe: Conceptualization (supporting); investigation (supporting); writing – review and editing . James A. Crossman: Conceptualization (supporting); data curation (supporting); formal analysis (supporting); investigation (supporting); methodology (supporting); validation (supporting); writing – review and editing . Edward A. Baker: Funding acquisition (supporting); investigation (supporting); project administration (supporting); resources (supporting); writing – review and editing (supporting). Nicholas M. Sard: Formal analysis ; methodology (supporting); software (supporting); visualization (supporting); writing – review and editing (supporting). Kim T. Scribner: Conceptualization ; formal analysis (supporting); funding acquisition (lead); investigation (lead); methodology (supporting); project administration (lead); resources (lead); supervision (lead); writing – original draft (supporting); writing – review and editing (lead).Funding for the project was provided by the Michigan Department of Natural Resources (DNR), the Great Lakes Fisheries Trust, Michigan State University Ag Bio Research, and the Partnership for Ecosystem Research and Management (PERM) cooperative program between the Michigan DNR and the Department of Fisheries and Wildlife at Michigan State University. TYD was supported by a Vietnamese Government Fellowship (Project 322).The authors declare that they have no conflict of interest to disclose.Table S1.Click here for additional data file.Figure S1Click here for additional data file.


Investigating how co‐designed knowledge can be translated to co‐produce a public health capacity‐building solution for difficult‐to‐engage population groups drawing on the co‐production experience of a prevention‐focused, capacity‐building mental health solution targeting primary producers.A qualitative study undertaken in rural and regional Victoria involving members of the design working group including project team (7px), digital design team (5px), marketing team (3px), and funding partner representatives. The study design involved reflective practice to collect data to identify the phases of co‐production and assess the design working group members' experiences. The analysis involved inductive coding using Braun and Clarke's thematic analysis.Identifying major points of divergence and/or convergence; enablers and/or constraints; and ways to better navigate and strengthen the co‐production process.Given members of the design working group, diverse skills sets divergence was experienced in all co‐production phases. Divergence was also experienced between the project team and the funding partner given the uniqueness of working conditions and requirements of workers in the primary production industry. The project team applied an iterative development process to project management; encouraging iterative cycles to create/test/revise among the teams, and with the funding partner, until each was satisfied with the end result (convergence).When developing a co‐created public health prevention campaign it is critical that the project team focuses on relationship building among the members of the design working group and ensures adequate resourcing, development of shared understanding of project goals and target audience, ongoing communication, and a commitment to working iteratively. Primary producers can be difficult to engage in public health and mental health prevention programsCo‐designing interventions can improve uptake, engagement, and ownership in difficult‐to‐reach populationsTranslating co‐designed knowledge into the co‐production of capacity‐building, online public health solutions can be challenging, due to the divergent skills sets, motivations, and professional languages of those involvedDiscusses how co‐designed design principles were translated and co‐produced into a prevention‐focused, capacity‐building mental health solutionIdentifies the enablers and constraints that a multidisciplinary team experienced during the co‐production processOffers strategies for successful collaboration when developing a co‐created public health prevention campaign1Farmers and fishers (hereafter termed primary producers) commonly work in environments involving high levels of uncertainty and low levels of job control, placing them at considerable risk of poor‐mental health.O'Reilly et al.The purpose of a co‐design methodology is to provide a structure to facilitate input from the group of affected people into the development of the proposed ‘solution’, so that it is user‐centred and stakeholder supported.How can co‐designed knowledge be translated to co‐produce a public health capacity‐building solution for difficult to engage population groups?In light of the above, this article aims to detail the experience of the co‐production process and document how the PPKN design working group undertook the solution build for the Campfire project. Details regarding the co‐design process and its outcomes have been published previously.22.1The PPKN commenced in April 2020 and concluded in January 2023, led by Australia's National Centre for Farmer Health and funded by the WorkSafe Victoria's WorkWell Mental Health Improvement Fund. The aim of the PPKN is to prevent work‐related risks to mental health among primary producers. To realise this aim, in June 2020 the PPKN project team commenced a co‐design process with primary producers and industry stakeholders, applying the seven‐step framework outlined by Trischler et al.A paper detailing the PPKN and the application of Trischler et al.'sFollowing the completion of the co‐production process, the PPKN project team retrospectively reflected on the process undertaken. Seven overlapping phases were identified . Two research assistants joined the team during the co‐production process (Author 6 and Author 7). All the project team members have a focus on translational research, with experience using community‐based participatory research approaches including co‐design. The digital design team has expertise in physical design, digital media and strategy and the team included five members including the co‐author (Author 8). The marketing team has expertise in graphic design, web design, marketing, advertising and illustration and comprises three members including the co‐author (Author 9). The project funding partner was WorkSafe Victoria's WorkWell Mental Health Improvement Fund—established to support workplace leaders to prevent mental injury and promote safe and mentally healthy workplaces. WorkWell recognised the need for more support in agriculture and worked with PPKN to ensure there was a project focused on the agriculture industry.2.3After identifying the seven co‐production phases, the project team split into sub‐groups (2–3 people) and allocated phases of the project in which they were closely involved. Sub‐groups identified the key activities undertaken, based on recall and project documentation . Author 1 then compiled narrative summaries of each phase which were sent to the co‐authors to check for accuracy. Co‐authors were then asked to assess their experience of participating in the PPKN design working group during each phase in which they were involved. Specifically, they were asked to: (1) Describe any major points of divergence (a drawing apart) and/or convergence (a coming together) experienced between the different teams; (2) Identify important enablers and/or constraints; and (3) Offer suggestions for better navigating and strengthening the co‐production process. Author 1 then collated the responses and thematically analysed them using Braun and Clark's inductive coding approach.2.4The PPKN project was approved by Deakin University's Faculty of Health Ethics Committee (HEAG‐H79_2020)3A description of the activities undertaken, and the experiences of the participating teams are included under each phase:3.1The co‐production process commenced in June 2020 with the project team delivering the ‘co‐design report’ to the digital design team . However, the personas and the brand narrative served as important elements that helped to drive convergence between all teams as they reminded everyone who the target audience was and what the purpose, objective and values of Campfire were.3.3The digital solution was developed to directly address work‐related factors on primary producers' mental health . Work‐related factors relevant to primary producers were mapped against the information gathered from the literature, expert interviews and the co‐design findings,Divergence was noted at points in the process of solution development, due to differences in expectations towards the delivery and communication of a WorkWell funded project. To navigate and negotiate the divergence, the project team worked closely with the funding partner and related stakeholders to gain better understanding of work‐related factors. The language was adjusted in, and re‐alignment to the work‐related factors occurred with, the elements of the Campfire topics. This resulted in a solution that closely aligned with and contributed to the evidence base of the broader WorkWell program, while remaining a focused and targeted intervention for primary producers.3.4The project team recognised a tailored solution was needed to engage the target audience, particularly given the multitude of factors that differentiated primary production from other workplaces . The unique nature of primary production contexts and distinctive requirements of primary producers, therefore, posed challenges to the project team in terms of aligning with the overall goals and approaches of the broader WorkWell program. As such, the project required re‐negotiation and re‐alignment of approaches to tailor solutions for primary producers, including the adaption of language, the inclusion of relatable peer stories, and a focus on expert‐informed practical strategies and solutions. The end result was able to reconcile the divergence and create intervention solutions that drew on the existing evidence base to prevent and manage work‐related risk factors specific to primary production contexts.3.5The digital design team—using the design brief (phase 1), along with the knowledge gained from phases 2, 3, and 4—developed a digital prototype. This prototype comprised a web‐based, text‐driven platform modelled on a campfire conversation and supported by the capacity to share and store images, links and resources. Following feedback and acceptance by the project team, the prototype was presented to the PPKN's Project Advisory Group (PAG) which included primary producers and industry representatives (many of whom had been involved in the co‐design process). A further online feedback workshop was held with a broader group of co‐design participants and industry stakeholders to assess the acceptability and face validity of the Campfire platform. As part of finalising the Campfire platform, the digital design team developed a list of potential features and asked the project team to rank their priority as either ‘must’, ‘could’, ‘should’ or ‘do not’ include .Divergence was experienced between the project team and the digital design team during this phase. While the project team was concerned with creating a digital design solution that met the project goals and drove end‐user engagement; the digital design team was also focused on delivering a novel solution with a creative aesthetically designed user experience. While an acceptable compromise was reached that met the project goals, the resulting level of complexity extended the project timelines and required some adjustment to practical considerations of the digital solution . Further adjustments were made after the launch of the digital platform (see Phase 6).3.6The Campfire platform had two phases of pilot testing . Alpha testing was conducted by the project team and initial feedback regarding faults and issues were provided to the digital design team. After addressing the initial feedback, Campfire underwent beta testing involving primary producers and industry stakeholders drawn from the earlier co‐design workshops. A broader call for community stakeholders increased the beta testing group. Participants involved in beta testing were provided with one of the personas (developed in phase 2), with instructions to reflect this target audience and complete specific tasks when testing the platform's functions and useability . The project team captured participants' feedback from the beta testing using a Google form which was then passed on to the digital design team to address. After changes were made , a soft‐launch of Campfire was made to provide the opportunity for identifying and rectifying any previously unidentified errors .The project team and digital design team experienced challenges during pilot testing. From the project team's side, the challenge was twice needing to identify, invite and coordinate a large group of test users and then collate their feedback under time constraints. From the digital design team's side, the challenges related to the novel platform design, requiring a more complex and extended testing process compared with more mainstream digital solutions .3.7A sub‐group of the project team  were responsible for overseeing the creation of Campfire's digital content and other complementary resources such as a blog and podcast series and other promotional materials. Initially, the blogs and podcasts were created to help build the audience for Campfire's bonfire Q&A events . These blogs and podcasts were also found to be an effective way to engage primary producers not accessing the interactive digital platform. This addressed an identified need from the co‐design findings—while digital communication was increasingly acceptable to primary producers, non‐digital communication methods  were also needed for those not wanting to engage digitally. Both the digital and complementary resources were developed iteratively between the project team sub‐group, the guest experts (including primary producers and topic experts), and the funding partner. This involved a process of feedback and review by the funding partner before finalisation and posting/publication. It also resulted in a hard‐copy brochure being developed to communicate the work‐related factors  to primary producers attending PPKN promotion events.Some divergence between the funding partner and the project team emerged around the choice of language and the focus of blog and podcast content. To navigate this process, the project team worked to transfer knowledge regarding work‐related factors into simple language and practical messaging that was relevant and relatable to the primary production contexts. The tailoring of language surrounding work‐related factors was especially important, considering the importance of communication and tailored messaging for developing shared understandings of complex subject matters, which had been specified by primary producers in the co‐design sessions.4In the PPKN co‐production process, divergence between the PPKN design working group's teams was anticipated by the project team given the known differing expertise and skill sets involved, the planned use of creative digital technologies and the diverse group of end‐users. The PPKN was a large‐scale and ambitious project directed at the whole primary production sector . In response to these convergence risks, the project team applied an iterative development process to project management; encouraging iterative cycles of create, test, and revise among the teams until each was satisfied with the end result (convergence). An iterative process can be time consuming and resource intensive and should be factored into initial timelines and budgets for projects engaging with multiple stakeholders.Despite being funded by WorkWell to implement learnings and contribute to the evidence base to improve general workplace mental health and wellbeing in Victoria, the uniqueness of working conditions and requirements of workers in the primary production industry meant that the expectations, approaches and objectives of the overall WorkWell program were not always applicable to the PPKN project. This created initial challenges in co‐designing and co‐production in alignment with WorkWell principles. Establishing a shared understanding of objectives between partners and stakeholders is vital to position a project to progress in a timely, focused and effective manner. This can be enabled by early‐stage project‐specific meetings . Followed by regular contract management meetings to present stakeholder's knowledge of the issue, the target audiences and conceptual frameworks being used, and to identify and address any significant differences in expectations and understandings throughout the co‐design and co‐production processes. Should any divergence be identified, it is crucial for all partners involved to establish a process to iteratively work towards convergence through knowledge sharing, conflict resolution, and problem‐solving systems.The project team needs to be conscious when contracting digital technology, marketing teams or other commercial partners for co‐production that the priorities, approach, and services required will differ from a co‐designed research/service delivery project . These differences (and resulting expectations) need to be communicated and understood by all parties and clearly articulated in the tender or invitation to quote documents, where possible.Involving commercial partners  in the early stages of co‐design would help build understanding of the context and the end‐users from the outset, creating a more time and budget‐efficient process of solution development. This would influence decisions relating to simplicity/complexity and the level of creativity needed for the digital solution.4.1This article reports on the enablers and constraints experienced by the teams involved in the PPKN design working group. There may have been different things to consider if different teams  had been involved, e.g., public health services. The solution development (and the resulting interplay of stakeholders) was influenced by the COVID environment. Considerations may have differed in a non‐COVID environment where face‐to‐face engagement between the teams would likely have occurred.5While the quality improvement measures suggested in this article are not necessarily novel, they are no less important to reinforce. Relationship building, adequate resourcing , shared understanding of project goals and the target audience, ongoing communication, and a commitment to work iteratively to meet project objectives in spite of varying stakeholder priorities are critical when developing a co‐created public health prevention campaign.CC: conceptualization; data curation; formal analysis; investigation; methodology; writing – original draft; writing – review and editing. AK: conceptualization; data curation; formal analysis; investigation; methodology; writing – original draft; writing – review and editing. TD: conceptualization; formal analysis; investigation; writing – original draft; writing – review and editing. KMDG: conceptualization; formal analysis; investigation; writing – original draft; writing – review and editing. JM: writing – review and editing. CM: writing – review and editing. SC: writing – review and editing. SH: software; writing – review and editing. JL: resources; writing – review and editing.The authors declare no conflict of interest.The Primary Producer Knowledge Network (PPKN) was funded by the WorkSafe Victoria's WorkWell Mental Health Improvement Fund.The PPKN project was approved by Deakin University's Faculty of Health Ethics Committee (HEAG‐H79_2020).


Mimulus guttatus) by leveraging a common garden experiment planted with range‐wide populations and observational studies of 11 local populations. In the common garden, 89% of seedlings died during the heat wave including >96% of seedlings from geographically local populations. Some populations from hotter and drier environments had higher fitness, however, others from comparable environments performed poorly. Observational studies of local natural populations drastically differed in the consequences of the heat wave—one population was completely extirpated and nearly half had a >50% decrease in fitness. However, a few populations had greater fitness during the heat wave year. Differences in mortality corresponded to the impact of the heat wave on soil moisture—retention of soil moisture throughout the heat wave led to greater survivorship. Our results suggest that not all populations experience the same intensity or degree of mortality during extreme events and such heterogeneity could be important for genetic rescue or to facilitate the distribution of adaptive variants throughout the region.Heat waves are becoming more frequent and intense with climate change, but the demographic and evolutionary consequences of heat waves are rarely investigated in herbaceous plant species. We examine the consequences of a short but extreme heat wave in Oregon populations of the common yellow monkeyflower ( We demonstrate that although heat waves may be devastating for certain populations in a region, not all populations experience the same intensity or mortality. This heterogeneity in selective pressures within and among populations may be important for genetic rescue or to facilitate the distribution of adaptive variants throughout the region. Annual populations of M. guttatus occur throughout western North America in inland areas with ephemeral water supplies such as rock walls, seepy meadows, and flood plains  How do local populations perform relative to more geographically distant populations during an extreme event? (2) Do extreme weather events favor populations whose historical environment more closely matches the extreme event? (3) Are the consequences of heat waves homogenous across a metapopulation?, and (4) If not, is heterogeneity predictable by variation in environmental characteristics between sites? We find that native populations performed poorly in our common garden, but some distant populations that historically encounter extreme heat more frequently have far higher fitness. Local populations also show considerable variation in responses to the heat wave with some populations avoiding negative fitness consequences entirely.Here we investigate how 22.1M. guttatus populations. We quantified the magnitude of this heat wave by comparing climate in 2019 to historic averages. We downloaded monthly averages of minimum, average, and maximum temperatures as well as average precipitation and precipitation as snow for each year from 1980 to 2019 from ClimateWNA  in unperforated 10″ × 20″ flats. We covered the flats with clear humidity domes, and cold‐stratified the seeds in the dark at 4°C. After 7 days of stratification, we moved the flats to the University of Oregon greenhouse with ambient light and temperature conditions. Plants were misted and germination was recorded daily. Following 7 days in the greenhouse, we removed humidity domes and plants were bottom‐watered as needed. After 14 days in the greenhouse, we randomized all pots into 12 blocks and transplanted seedlings directly into the field site. Microsite variation in water availability is high at this site with a natural population of We surveyed survival and flowering for each plant every other day. Survival was defined as having any living green tissue in leaves, stem or meristem . No plant that was recorded as dead appeared later in the growing season as alive. To assess fecundity, we counted the number of flowers, collected all mature calyxes, and counted the seeds they contained. Below we report “inclusive number of flowers” as the total number of flowers where plants that did not survive or flower counted as zeros and “inclusive number of seeds” as the number of seeds produced where plants that did not produce seeds counted as zeros. We report both metrics because the number of flowers better includes fitness contributions through male fecundity while the number of seeds better represents female fecundity.2.3M. guttatus range using linear mixed models and generalized linear mixed models (LMMs and GLMMs) implemented with the lmer and glmer functions in the lme4 v1.1‐27.1 package  every 7–14 days from snowmelt until population senescence. On each visit, we counted the number of vegetative, flowering, and senesced plants as well as measured volumetric water content with an SM150T soil moisture sensor (Dynamax). Grid locations were chosen within sites to encompass the natural variation within the site while only using areas with high concentrations of M. guttatus seedlings.We selected 11 natural populations distributed across an elevational gradient of ~600 m in a 10 kmAppendix . In eachWe examined how the number of individuals in each grid changed before, during, and after the heat wave to assess the mortality associated with the heat wave. To examine whether differences in soil moisture were driving differences in mortality between plots, we used an LMM to model whether the amount of mortality experienced in a grid during the heat wave was associated with the volumetric soil water content before the heat wave. Population was treated as a random factor in these models. Statistical significance of the fixed factors was assessed with lmerTest v3.1‐3 using Satterthwaite's degrees of freedom method  using linear regressions implemented through the lm function. Differences in seed production between years were calculated from population averages.We examined the influence of the heat wave on fecundity using observational data collected at the end of the 2018 and 2019 growing seasons from 12 natural populations. Nine of these populations were the same ones as described above Appendix . We chos33.1χ2 = 141.1, p < .001). Survivorship in blocks ranged from 0% to 77.3% and only three blocks had >15% survivorship. Blocks where soil dried out later in the heat wave had higher survivorship suggesting that death was due to a combination of limited water availability and heat stress .Climate patterns in 2019 in the Central Oregon Cascade Mountain Range closely resembled historic monthly normals for both temperature and precipitation Figure . However3.2χ2 = 22.9, p = .01, Appendix There were significant differences in survivorship among populations planted in the common garden following the heat wave  at locations across Browder Ridge. Indeed, the heat wave did cause mortality for every population surveyed except one (MBR). The number of individuals in 23 of 24 grids declined during the heat wave  and number of seeds . The majority of natural populations had lower fecundity during the year of the heat wave (2019). In the populations that did worse in 2019 than in 2018, the number of flowers and the number of seeds were reduced by an average of 36% and 41%, respectively  and 2019 (an extreme heat wave early in the growing season). There was a significant population‐by‐year effect on both number of flowers  as the heat wave occurred just as experimental plants were finishing establishing (transplanted 7 days prior to the start of heat wave). While this could be considered mortality due to establishment shock, we suggest this is relatively unlikely given our observations in nearby natural populations. That is 11 of the 12 natural populations had drastic declines in soil moisture and high mortality during this period Figure . Rates o4.2While mortality was high within both our common garden and natural populations, the fact that a minority of plants did survive and reproduce suggests there may be traits that facilitate survival. We expect populations from areas with historic climates that more closely match the extreme event to have higher fitness than native populations that rarely encounter such conditions – that is, an adaptation lag  do not match previous patterns found at the same location. We conducted a similar common garden experiment at the same site with many of the same populations in 2014 ; formal analysis (supporting); investigation ; writing – review and editing . Anna Scharnagl: Conceptualization (supporting); investigation ; writing – review and editing . Andrea K. Turcu: Investigation ; writing – review and editing . Courtney M. Patterson: Investigation ; writing – review and editing . Nicholas J. Kooyers: Conceptualization (lead); formal analysis (lead); writing – original draft (lead); writing – review and editing .Funding for this research came from the University of Louisiana, Lafayette and NSF grant DEB‐2045643 to NJK.The authors declare no competing interests that may have influenced this manuscript.


National Cancer Institute cancer centers (NCICCs) provide specialized cancer care including precision oncology and clinical treatment trials. While these centers can offer novel therapeutic options, less is known about when patients access these centers or at what timepoint in their disease course they receive specialized care. This is especially important since precision diagnostics and receipt of the optimal therapy upfront can impact patient outcomes and previous research suggests that access to these centers may vary by demographic characteristics. Here, we examine the timing of patients' presentation at Moffitt Cancer Center (MCC) relative to their initial diagnosis across several demographic characteristics.A retrospective cohort study was conducted among patients who presented to MCC with breast, colon, lung, melanoma, and prostate cancers between December 2008 and April 2020. Patient demographic and clinical characteristics were obtained from the Moffitt Cancer Registry. The association between patient characteristics and the timing of patient presentation to MCC relative to the patient's cancer diagnosis was examined using logistic regression.Black patients (median days = 510) had a longer time between diagnosis and presentation to MCC compared to Whites (median days = 368). Black patients were also more likely to have received their initial cancer care outside of MCC compared to White patients . Furthermore, Hispanics were more likely to present to MCC at an advanced stage compared to non‐Hispanic patients (OR [95% CI] = 1.28 [1.05–1.55]).We observed racial and ethnic differences in timing of receipt of care at MCC. Future studies should aim to identify contributing factors for the development of novel mitigation strategies and assess whether timing differences in referral to an NCICC correlate with long‐term patient outcomes. There are racial differences in timing of receipt of care at our NCI cancer center. Black patients were more likely to have initial care outside of our center, while Hispanic patients were more likely to present with advanced stage. These designations are awarded to institutes deemed by the NCI to meet rigorous standards for multidisciplinary cancer care.In addition to access to clinical trials, data suggest that patients may receive care more guideline‐based care at NCICCs compared to community settings,Relatively less is known about patient or disease characteristics associated with the timing of care at these NCICCs. This is especially true for underrepresented minorities for whom disparities in prevention and treatment remain stark.To evaluate possible disparities in early care at NCICCs, we sought to determine patient characteristics associated with receipt of care at our NCICC. Specifically, we examined the timing of patients' presentation to our center relative to their initial diagnosis across several demographic characteristics among patients with cancers.22.1n = 12,334), colon cancer (n = 3086), lung cancer , melanoma (n = 8821), and prostate cancer (n = 6694). The study adheres to the tenets of the Declaration of Helsinki and was reviewed by the Advarra Institutional Review Board and determined to be exempt, Pro00044703.We conducted a retrospective study among Moffitt Cancer Center (MCC) patients to examine the association between patient characteristics and the timing of receipt of care at our NCICC relative to the patient's cancer diagnosis. Patients were included in the study if they (1) were diagnosed at aged ≥18 with any of the five screening‐detectable cancers that reflect the largest burden in the MCC catchment area , (2) presented for the first time at MCC between December 2008 and April 2020, and (3) received a diagnosis and/or active treatment at MCC. The final sample size included 41,539 patients comprising those with breast cancer  summary staging system were selected for the current analysis since it was available at both the time of diagnosis and presentation to MCC. Patients were categorized as living in the 15‐county MCC catchment area (2016–2021) at the time of presentation.2.3n = 32,608). Non‐analytic cases were defined as a case in which the patient's first contact at MCC follows prior treatment at a different facility (n = 8931). The stage at cancer diagnosis relative to the stage at presentation to Moffitt was considered, and the subgroup of patients whose tumor stage at presentation was more advanced than their original stage at diagnosis was identified and compared to those who had stage concordant at presentation. Finally, within non‐analytics, length of time between date of diagnosis and date of presentation was evaluated.Several approaches were taken to define groups of patients whose receipt of care at MCC could be considered “delayed”. First, the timing of presentation to Moffitt relative to the disease course was considered by assessing patients' class of case, as recorded in the Cancer Registry, including analytic and non‐analytic cases. Analytic cases were defined as a case in which the patient is diagnosed and/or receiving first course treatment at MCC  those whose tumor stage at presentation to MCC was the same as their tumor stage at initial diagnosis (concordant stage at presentation) (2) those whose tumor stage at presentation was more advanced than that at diagnosis, (3) those whose tumor stage at diagnosis was more advanced than that at presentation, and (4) those whose stage data were missing at either time point. Stage distributions were also stratified by types of cohort‐defining cancer. Of note, the tumor stage at diagnosis could have been more advanced than the stage at presentation to Moffitt if the patient received treatment elsewhere (prior to their presentation at Moffitt), resulting in a tumor stage that was less advanced at presentation than the original stage at diagnosis.The characteristics of patients with more advanced stage at presentation were compared to the non‐analytic patients who had concordant stage at presentation. Cohort‐adjusted logistic regression was used to estimate the association between each characteristic and whether a patient had a more advanced stage at presentation. Subsequently, a backward elimination process was performed on a multivariable logistic regression model including cancer type and all factors that were significantly associated with a more advanced stage at presentation. An interaction term for age and payment method was also included in the model. In addition, the univariable logistic regression models were stratified by cancer type.The time between initial cancer diagnosis and presentation at MCC was also analyzed among non‐analytic cases. The median and interquartile range of the number of days between the date of cancer diagnosis and the date of presentation were summarized for each group. Wilcoxon rank‐sum and Kruskal–Wallis test were used to compare the lag time as appropriate. To further explore disparities in the time between initial cancer diagnosis and presentation to MCC, analyses were conducted examining two sub‐intervals: (1) time between cancer diagnosis and initiation of first course treatment and (2) time between the end of first course treatment and presentation to MCC. Patients were included in this exploratory analysis if they received any of the following treatment modalities as a part of their first course treatment outside of Moffitt: chemotherapy, hormone therapy, immunotherapy, radiation, surgery, and organ transplantation. Time between cancer diagnosis and initiation of first course treatment was compared across patient groups as defined by ethnicity using Wilcoxon rank‐sum test and by race using Kruskal–Wallis test, followed by post hoc analysis with adjustment for multiple comparisons. The same methods were used to compare time between the end of first course treatment and presentation to MCC. All analysis were performed using R version 4.0.2 (RRID: SCR_001905).Lastly, a heatmap‐like plot was generated to summarize the associations between patient characteristics and each of the three proxy indicators of delayed receipt of care described previously.33.1After adjusting for cancer type, patients ≥65 at time of cancer diagnosis were less likely to be non‐analytic cases  as compared with patients diagnosed before age 65 Table . Furthern = 933, 52%) progressed from regional to distant metastasis. A similar pattern was observed when stratifying the stage distributions by cancer type, with most analytic patients having stage concordant at presentation regardless of cancer type . No statistically significant differences were observed between White and Asian or other/multiple races or between Hispanic and non‐Hispanic patients. Longer time intervals were observed between the end of first course treatment and presentation at MCC among racial minorities  as compared with White patients (median = 516.5 days). However, this result did not reach statistical significance . The time between end of first course treatment and presentation to Moffitt was significantly longer among Hispanic patients (median = 604 days) compared to non‐Hispanic patients .Time between cancer diagnosis and the initiation of first course treatment was significantly longer among Black patients (median = 16.5 days) as compared to White patients , most individuals stated they would be willing to travel significant amounts to access high‐volume or high‐quality cancer care. However, when participants were asked to identify specific logistical barriers that would prevent them from traveling 1‐hour to access high‐quality cancer care, participants cited barriers such as parking costs, drive time, and cost of lodging.To this end, our data demonstrates a few notable results. First, our catchment area population was more likely to be analytic cases compared to the population residing outside of the catchment area. This is not surprising since prior data suggests travel time to a NCICC is one of the most influential determinants to receipt of care.Interestingly compared to non‐Hispanic White patients, Black patients were more likely to be non‐analytic cases and have the longest time interval between diagnosis and presentation to MCC. Among non‐analytic cases, Hispanic patients presented with more advanced stage compared to non‐Hispanic patients and a longer time interval between end of first course treatment and presentation to MCC. While our study could not determine the underlying reasons for these differences, it is possible that structural barriers including but not limited to lack of access to reliable transportation, insurance coverage, and other socioeconomic or geographic factors contributed to our findings. While to our knowledge no previous studies have examined racial and ethnic differences in the timing of receipt of care to an NCICC, studies have analyzed general patterns by different demographic groups, though the results are somewhat mixed. One study of the California Cancer Registry found no difference in utilization of NCICCs between Black and White patients, though there was an inverse association between Hispanic ethnicity and use of an NCICC.Additionally, Medicare and Medicaid patients were more likely to be non‐analytic cases compared to patients with private/managed insurance, possibly reflecting delays in insurance approvals of referrals. Of note, access to NCICC may be limited by federal marketplace plans. Only 41% of provider networks initially available on the federal marketplace through the Affordable Care Act included a NCICC.Interestingly, males were more likely to be non‐analytic cases as compared with females in our study. Men are known to participate less in recommended cancer screenings,Cancer registry data has many strengthens as it employs uniform case ascertainment, documented stage at presentation and at diagnosis. However, we acknowledge several limitations. First, our analysis was limited to Moffitt Cancer Center, and our findings may not be generalizable to other NCICC's. However, other NCICC's can replicate our analysis using their own Cancer Registry data to examine demographic factors associated with receipt of care at their institutions, highlighting potential disparities most important to address locally. Second, cancer registry data does not capture information on referral source or second opinion visits. Future analyses are planned to examine referral patterns using multiple institutional data sources beyond the Cancer Registry. Our analysis of social determinants of health was limited to insurance status, while other important variables such as transportation costs, childcare, or other issues that may make it difficult for a patient to receive care an NCICC were not available. Future studies will seek to elucidate the factors contributing to the observed differences in timing of receipt of care at an NCICC.In summary, our study represents an innovative use of cancer registry data to analyze differences in timing of receipt of care at an NCICC. The use of cancer registry data can be leveraged for future studies assessing whether timing differences in referral to an NCICC correlate with long‐term outcomes will be important in understanding the translational impact of these observed disparities. Overall, our study underscores the utility of using cancer registry data to better understand disparities in timing of access to cancer care at specialized centers and may help inform targeted interventions to improve access in the future.Kedar Kirtane: Conceptualization ; funding acquisition ; writing – original draft . Yayi Zhao: Conceptualization ; data curation ; formal analysis ; methodology ; writing – original draft . Rossybelle P Amorrortu: Conceptualization ; project administration ; writing – review and editing . Lindsay Fuzzell: Conceptualization ; writing – review and editing . Susan Vadaparampil: Conceptualization ; writing – review and editing . Dana Rollison: Conceptualization ; methodology ; project administration ; supervision ; writing – review and editing .This work has been supported by a Miles for Moffitt Grant and the Collaborative Data Services Core at the H. Lee Moffitt Cancer Center & Research Institute, a comprehensive cancer center designated by the National Cancer Institute and funded in part by Moffitt's Cancer Center Support Grant (P30‐CA076292).Rossybelle Amorrortu, Lindsay Fuzzell, Yayi Zhao, and Susan Vadaparampil declare they have no conflicts of interest. Kedar Kirtane owns stock in Seattle Genetics, Oncternal Therapeutics, and Veru. Dana Rollison serves on the Board of Directors for NanoString Technologies, Inc.