Combining Modern Pharmacology with Integrative Medicine: A Biopsychosocial Model for Comprehensive Pain Care

*Agnes Mazic De Sonis*

#### **Abstract**

The medical community recognized last decennia the multidimensional nature of pain and proposed multimodal biopsychosocial management. The most compelling reason to embrace integrative pain strategies is to mitigate patient risk. For patients with chronic pain and pain refractory to conservative medicine, it is essential to assess all factors involved with the chronicity. With significant themes, nutrition and microbiome, neuroplasticity, homeostasis, and the side effects of medication, acupuncture has progressively gained a place in this multimodal evaluation. Therapeutic multimodality approaches the perspective of physiological rehabilitation and chronobiological improvement of the quality of life. Illustrated by various clinical situations, the objective of management is to seek a synergy in the mechanisms of action of treatments to improve quality of life and reduce the need for xenobiotics and, consequently, the side effects. The mechanism of action of integrative medicine, and acupuncture improved with a better understanding of genetics, and epigenetics. As opposed to sham and placebo, acupuncture activates other brain regions. In controlled trials, the strict inclusion and exclusion criteria result in the treatment of a "selected" patient population, which is not always comparable to the patients seen in daily practice. The integrative approach is better illustrated by case reports.

**Keywords:** acupuncture, nutrition, microbiome, p4medicine, personalized medicine, integrative

#### **1. Introduction**

Even for modern medicine, chronic pain remains a complex, multi-faceted problem of nociception, inflammation, and abnormal physiology in the nervous system. Thanks to the knowledge of epigenetics, it becomes clear that environmental factors such as nutrition and chronobiology can modify the parameters involved in all sensitization mechanisms in chronic pain diseases. The deranged sensitization mechanisms suggest restoring the hypersensitive structures to their normal status besides the analgesic treatment.

While more research is needed to understand the progression from acute to chronic pain, the limited pain management strategies have not addressed the scope of pain.

Increased costs and lack of evidence of efficacy are not, according to the physicians (ACP) Clinical Practice Guideline, evidence-informed, comprehensive pain care while conceding that past strategies generally, and the use of opioid medications specifically, have not remedied but rather exacerbated chronic pain, abuse, addiction, illness behavior, and disability [1].

Awareness of serious adverse effects of medications is growing, including the escalating rates of accidental overdoses of prescription opioids and the development of opioid tolerance and hyperalgesia [2].

IASP 2023 global defines integrative pain care as temporally coordinated, mechanism-guided, individualized, and evidence-based integration of multiple pain treatment interventions. Considering the ever-growing burden of chronic pain, current pain management models frequently do not address the clinical problem. The complexity of chronic pain justifies a bio-psycho-social framework, integrating different management and treatment approaches is preferred.

#### **2. Pain chronobiology and epigenetic regulation**

A total of 30% genetic and 70% epigenetic factors, such as nutrition and intestinal flora, social, psychological, and affective define the status of an individual [3]. The sensibility for pain is affected by 20 genes. These are also responsible for the variation in reaction to pharmacologic treatment (see **Figure 1**) [5].

The ignition or blocking of specific genes is epigenetically regulated. It is also sensitive to environmental factors [5].

Intra and extracellular homeostasis regulates the peripheral sensitization of the primary nociceptors. Inflammation activates the bidirectional signaling that it modulates. Even though there is no immunological response, certain bacterial infections could be accompanied by a hyperalgesic state (see **Figure 2**) [6].

Pharmacological treatment of chronic pain has dose-dependent side effects, including opioid tolerance, addiction, and even death. Chronic pain involves neuroplastic changes, and neuroinflammation becomes a key question in central sensitization (**Figure 3**).

Pain induces arousal and triggers other neurobiological stress sequels, thus disturbing sleep and enhancing pain sensitivity. Disturbed sleep or pain may induce a cycle whereby both components stabilize or augment each other. Therefore, management of sleep disturbance may alleviate pain, whereas pain relief may restore sleep and enhance long-term pain relief.

Treatment should target the different mechanisms of pain and may require a combination of treatment options. Combining therapies, such as acupuncture, with traditional pharmacology is still in its infancy.

Acupuncture influences the opioid and cannabinoid system by releasing endogenous receptor ligands. Low-dose naltrexone also acts on both systems and upregulates the opioid and cannabinoid receptors.

Dietary choices and drug use (proton pump inhibitors, NSAIDs, steroids, antibiotics, and hormones) can influence inflammation by altering the microbiome and gut permeability. The balance of microorganisms can affect the absorption of nutrients, drugs, and the function of the immune system leading to low-grade inflammation.

*Combining Modern Pharmacology with Integrative Medicine: A Biopsychosocial Model… DOI: http://dx.doi.org/10.5772/intechopen.112906*

**Figure 1.**

*Influences of the epigenetic modulation system. From Ref. [4].*

**Figure 2.** *Interactions leading to vulnerability for pain.*

**Figure 3.** *Schema of gut-brain interaction from [7].*

One day after morphine treatment, there is a significant shift in the gut microbiome and metabolome. Morphine-induced gut microbial dysbiosis exhibited distinct characteristic signatures. Drug-microbiota dynamics could help to identify drug-drug interactions and explain inter-individual variation in drug efficacy and adverse effects. The gut microbiome can affect all classes of drugs.

The gastrointestinal microbiome plays a significant role in responses to opioids, including the development of tolerance.

The neuro-immune interactions induced by morphine have direct intestinal functional consequences. Morphine disrupts gut barrier function in a toll-like receptor (TLR)-dependent manner [8]. Low-dose naltrexone (LDN) acts on various gut mechanisms.

Analgesic tolerance to opioids induced by the gut-brain interaction suggests that peripheral mechanisms from the gut can profoundly affect the central control of opioid function. The answer to treatment can be modulated by genetic variations and the inter-individual differences in the bacterial flora of the human digestive tract. The pharmacokinetics of drug metabolism was redefined by the progress in

*Combining Modern Pharmacology with Integrative Medicine: A Biopsychosocial Model… DOI: http://dx.doi.org/10.5772/intechopen.112906*

understanding the host-microbial interaction and has improved the management of drug (ab)users.

Acupuncture influences different molecules and receptors, such as GABA, glutamate, and its other receptors (AMPA, NMDA), serotonin (5HT), and the opioid system. The treatment objective is addressing pain and preventing chronicity, focusing on drug and non-drug strategies. Therapeutics directed at maintaining microbiome homeostasis during opioid use may reduce the associated comorbidities.

#### **2.1 Integrative pain medicine and mitigation of risk**

The overlap with conventional care is growing as the scientific basis for these therapies expands. Integration across the lifespan to include personal, predictive, preventive, and participatory care.

Personalization of treatment usually means targeting a smaller subset of patients who share a particular phenotype. The economic or financial viability of stratified medicine versus empiric medicine (a medicine prescribed to all patients with a specific condition) was evaluated by Trusheim and Berndt [9] and Ozdemir et al. [10].

Personalized medicine goals require knowledge of which treatment is best for each individual, and promises increased efficiencies for health care systems. Much emphasis in developing customized therapies has been on genetic polymorphisms and blood biomarkers [10]. The predictive capacity of the data pattern must be defined. Determining clinical variables by interview remains the most helpful tool available to a treating physician for selecting the best treatment options on a case-by-case basis. Several recent studies note the need for new models and frameworks that can consistently provide professionals and consumers with helpful knowledge that physicians can meaningfully apply [11].

#### *2.1.1 Acupuncture*

Under the premise of selecting acupoints along the meridians and adopting reinforcement and reduction manipulations, acupuncture will bidirectionally regulate the clinical symptoms and signs.

The same stimulation parameters applied to the same acupoint or nerve may result in opposite regulation (restoring homeostatic balance or normalizing function), the so-called "bidirectional regulation".

The peripheral lesions around the needle trigger physiological reactions and initiate a cascade of survival reactions. Via the reflex of the axon due to the increased blood flow in the muscle, Calcitonin Gene-Related Peptide (CGRP) and nitrous oxide (NO) are released after manual acupuncture and contribute to tissue healing [12, 13].

 Acupuncture normalizes physiological homeostasis and promotes self-healing. The primary nociceptors are complex in the ligand expression of neurotransmitters and receptors, enabling autocrine and paracrine interactions.

Primary nociceptors generate bidirectional efferent messages toward the innervated tissues, and can modify (facilitate or inhibit) sensory information even before transmission to the central nervous system.

Nociceptors seem to have a mind of their own (see **Figures 4** and **5**) [13].

Pain control might be influenced by the modulation of different molecules and receptors such as GABA, glutamate, and its other receptors (AMPA, NMDA, etc.),

**Figure 4.** *Hyperalgesia at a cellular level.*

the serotonin (5HT) system, the opioid system, norepinephrine (NE), cholinergic receptors, etc. Low-frequency electroacupuncture (EA) has a better effect than a high frequency (100 Hz).

Bidirectional regulation is a unique phenomenon of acupuncture therapy, seen in multiple systemic, cellular, and molecular functional systems. Not all acupoints unconditionally produce the bidirectional regulatory effect, and the corresponding factors remain to be investigated. The body's homeostatic regulation can achieve bidirectional regulation by acupuncture or peripheral stimulation in different functional states. It is not a simple physiological response but a complex pathophysiological process [15, 16].

Acupuncture stimulates brain responses in cortical and subcortical regions, associated with modulation of the pain sensation and perception, including activation in the sensorimotor cortical and deactivation in the limbic-para limbic-neocortical network as demonstrated with functional neuroimaging studies [17]. It is postulated that the therapeutic response to acupuncture, such as down-regulation of inflammation and autonomic nervous system-mediated pain relief, is provided by a mechanistic pathway of the autonomic nervous system.

Event-related (er)-fMRI is used to evaluate the brain correlates of acupuncture stimulation, it seems to be associated with different autonomic nervous system outflow responses to needle stimuli and may result from other sensations elicited by stimuli at different bodily locations [18]*.* In vivo μ-opioid receptor (MOR) binding effects of traditional Chinese acupuncture versus sham acupuncture were found in chronic pain patients diagnosed with fibromyalgia [17]*.*

*Combining Modern Pharmacology with Integrative Medicine: A Biopsychosocial Model… DOI: http://dx.doi.org/10.5772/intechopen.112906*

#### **Figure 5.**

*Interactions at the nerve endings [14].*

#### *2.1.2 Nutrition and microbiome*

In addition to the severity of the underlying condition, interindividual variability in chronic pain depends on many factors, including its sociocultural context, patients' genetic backgrounds, psychological factors, and pathophysiology, that can be modulated and monitored by altering nutritional habits [19]. Specific nutritional deficiencies can be associated with pain states. A study discovered that patients with pain with insufficient vitamin D levels needed twice the dose of opioids for twice as long as patients without a deficiency.

Many different types of elimination diets can be useful for patients to try.

Food and nutrition are foundational tools in treating painful and inflammatory conditions. Compelling evidence shows the benefits of a healthy diet composed mainly of unprocessed, plant-based foods.

Sugars and facts may feed into many anabolic and catabolic pathways, the handling of the body of nutrients depends on strategically positioned metabolic sensors that link the intrinsic nutritional value of a meal with intermediary metabolism.

Assessing the nutritional status is a cornerstone of integrative pain medicine. Dietary choices increase or decrease inflammation. Free-radical damage of tissues, induced by inflammation, impedes healing mechanisms, and reduces pH to levels where normal enzymatic reactions are no longer optimized. Inflammation can be reduced by an anti-inflammatory diet, such as the Mediterranean diet—which is high in vegetables, fruits, whole grains, fish, and healthy oils but low in meat (**Figure 6**) [21].

**Figure 6.** *Schema of microbiota regulation [20].*

#### *2.1.3 The effects of drug therapy on the gut microbiome*

The individual diversity of the gut microbiome promotes inter-individual variations with pharmacotherapy, drug-induced toxicity, and efficacy.

The gut microbiome is affected by drug effects and the GI tract environment can be altered (e.g., pH and transit time), mucosa integrity, host and bacterial metabolic aqctivity, and the production of microbial metabolites. These changes can have secondary effects on the microbiome and cause drug-drug interactions. Drugs may also challenge both the integrity and permeability of the intestinal mucosa.

#### *<IP_ADDRESS> Drugs and polypharmacy*

The combined use of non-steroidal anti-inflammatory drugs (NSAIDs) and PPIs differentially influenced the relative abundance of Bacteroides spp. and Erysipelotrichaceae spp. Compared to NSAIDs alone, the co-administration of drugs may precipitate shifts in the composition of the microbiota to favor the abundance of microbial taxa that have a metabolizing capacity for those drugs [22].

#### *<IP_ADDRESS> Effect of diet-induced changes on the gut microbiome and drug pharmacokinetics*

Drug pharmacokinetics may be modulated by probiotics by changing the composition or metabolic activity of the gut microbiota. Probiotic treatment was shown to increase the microbiota-mediated degradation of the antipyretic and

*Combining Modern Pharmacology with Integrative Medicine: A Biopsychosocial Model… DOI: http://dx.doi.org/10.5772/intechopen.112906*

analgesic paracetamol, which may be mediated by probiotic-induced modulation of gut microbial enzyme activity.

Some patients are more at risk for food-drug interaction, such as chronic disease, elderly, malnourished, infant, and pregnant women.

Meanwhile, examining and explaining how gut microbiota regulates drug metabolism and toxicity will assist personalized medicine and facilitate strategies for creating new drugs with desired functionality.

#### **2.2 Towards circuit-based tVNS: translational approaches**

It is important to estimate the independent effects of the disease or drug treatment in animal and human studies, as both the CNS-related disease itself and the pharmacological treatment of the disease can alter the composition of the microbiota.

This microbiome impacts the properties and function of microglia involved in pain sensitization. To maintain homeostasis, the vagal nerve (VN) actively participates in bidirectional interactions between the gut microbiome and the brain. VN electroacupuncture promotes the expression and localization of junction proteins, decreasing intestinal permeability and protecting the intestinal epithelial barrier. Complex reflexes, such as the autonomic reflex, can be used to explain some therapeutic effects of acupuncture.

Administration of pre/probiotics to modify vagal nerve function could be a promising strategy for treating central nervous system disorders (**Figure 7**).

In human studies, the vital role of the VN in modulating food intake, energy metabolism, and glycemic control has been demonstrated more recently [23–27]. Across disciplines the pathophysiology of several disorders is attributed to the VN on a behavioral and psychological level; VN stimulation, remarkably non-invasive VN stimulation, has been studied, allowing a better understanding of the mechanisms by which VN stimulation exerts psychological and physiological effects. A more important pathway for acupuncture stimuli is via the autonomic center in the brain that works to up or down-regulate the sympathetic or para-sympathetic output. Neuroendocrine and neuroimmune pathways are also crucial for maintaining the stability of various functional systems in the body, and they can be affected by acupuncture stimulation.

#### *2.2.1 Nutraceuticals and others*

The purified products derived from plants, animals, microorganisms (e.g., essential fatty acids and enzymes), and marine sources (e.g., glucosamine, chitosan, fish oils) are called nutraceuticals. They are sold in medicinal forms e.g., tablets, capsules, and powders. The bioactive agents the nutraceuticals deliver may also be obtained through a healthy diet. They provide, however, the advantages of a formulation that promotes the absorption and the physiological effect [19].

#### *<IP_ADDRESS> Curcumin*

Hu et al. [28] recently determined that curcumin attenuates opioid-induced hyperalgesia by inhibiting Ca2+/calmodulin-dependent protein kinase II α activity and found that a nano-formulation of poly(lactic-co-glycolide)-curcumin-curcumin may reverse opioid-induced hyperalgesia by inhibiting caMKIIa and downstream signaling.

**Figure 7.**

*The multiple bidirectional communication routes between the brain and the gut microbiota. These routes include the vagal nerve, the hypothalamic-pituitary-adrenal axis (HPA), cytokines produced by the immune system, tryptophan metabolism, and short-chain fatty acid production. Adopted from [16].*

Curcumin induces mitochondrial biogenesis, and has a direct activity on reactive oxygen species, and induction of NRF2. It regulates the epigenetic patterns and has a synergistic activity on drugs used to treat different painful conditions. The low bioavailability of curcumin can be improved by bio-optimization techniques, thus increasing the therapeutic and preventive potentials of the natural substance [29, 30].

*Combining Modern Pharmacology with Integrative Medicine: A Biopsychosocial Model… DOI: http://dx.doi.org/10.5772/intechopen.112906*

**Figure 8.**

*Activation of microglia by toll-like receptor (TLR) agonists and by palmitoylethanolamide (PEA). Adopted from [31].*

#### *<IP_ADDRESS> PEA palmitoylethanolamide*

Glia may produce their own endogenous "painkillers" and anti-inflammatory agents through their own modulators. These modulators decrease the winding-up mechanisms in neuropathic pain. Anandamide and its sister molecule PEA are such modulators, and induce a "winding down" in chronic and neuropathic pain and neuroinflammation. Both molecules are classical autacoids, fulfilling the three criteria required for autacoids of lipid transmitters.

PEA is a modulator that reduces pain by decreasing winding-up mechanisms in neuropathic pain and neuroinflammation (**Figure 8**).

#### *<IP_ADDRESS> Low-dose naltrexone*

Within a specific dosage window, opioid antagonists such as naltrexone can exert a "paradoxical" analgesic effect. Low-dose naltrexone (LDN) produces the modulation of neuro-inflammation, and stimulates the glial cells to release inflammatory chemicals in the central nervous system. The dosage producing these effects is low compared to the dosage approved for all alcohol and opioid dependency. The pharmacological actions enhance the analgesic effects of endogenous opioids and cannabinoids. Naltrexone modulates the toll-like receptor 4, NO, and filamin A. LDN is safe, with very few side effects, and recent clinical pilot trials in fibromyalgia and multiple sclerosis showed pain reduction and quality of life enhancing impact [32]. It also improved pain tolerance in cold pressor tests and the ability of post-detoxification patients to relate interpersonally with other participants in human relationships (**Tables 1** and **2**).

**Table 1.**

*Summary of clinical experience with low-dose naloxone/naltrexone. Adopted from [33].*

#### **3. Observational studies to evaluate the effectiveness of healthcare**

The fundamentals of neurophysiology learn that the revalidation of the main chronobiological rhythm results in regulating sleep, food, and the vicious circle involved in pain sensitization.

Although randomized controlled trials are considered the most valuable method for proving the efficacy of a treatment. This method cannot be applied to every treatment. Black [46] discusses the advantages and disadvantages of strictly *Combining Modern Pharmacology with Integrative Medicine: A Biopsychosocial Model… DOI: http://dx.doi.org/10.5772/intechopen.112906*

#### **Table 2.**

*Clinical experience on LDN in multiple sclerosis. Adopted from [33].*

regulated randomized controlled trials (RCTs). Measuring treatment outcomes of one intervention in patients with complex diseases for whom it would be unethical to drop most ongoing treatments. The numbers to be included in RCTs for demonstrating superiority in effect are too small to identify sometimes rare side effects. The blinding in RCTs cannot be maintained sufficiently long to assess the long-term impact. Building evidence is often a step-wise process, where an effect is noted and reported in a case report. These findings can be confirmed in retrospective and prospective studies, and if possible, the effect can be compared to a placebo or another treatment in an RCT.

The debate regarding these research design issues within conventional medicine has risen in parallel with the growing emphasis on team-based medicine and integrative medical teams for "evidence" of effectiveness and efficacy to meet the standards of "evidence-based medicine."

These standards are predominantly set out for pharmacological treatment, but the EBM model does not evaluate all parts of acupuncture efficacy and strategies in researching complex interventions.

The «whole system» methodology opens the research on Integrative Medicine efficacy with enhanced EBM validation.

Internal and external validity address the usefulness and effectiveness of a treatment. They are complementary and must be addressed separately in different studies. The results must be seen together. The hierarchy of evidence is one of the internal efficacies, not of evidence in general. Other research methodologies must be used and validated.

The results of observational studies help to target treatments and provide information for future research. The mechanisms of action could be elucidated by basic research, and meta-regression could better explain variability in response. Combining the evidence from different sources in a decision-analytical modeling can be used for economic evaluations [47].

#### **4. Conclusions**

Pain management is shifting from a model of highly specialized pain care to multimodal evidence-informed options fitted to a patient's whole experience of pain and therapeutic goals. Ideas changed due to the emerging science about the impact on pain states by the microbiome, mitochondria, fascia, glia and neuroplasticity, and movement disorders. Evidence-informed practice is based on evaluating and disseminating current research, including biological, medical, and behavioral science, secondary to pain for future pain treatments.

Emerging epigenetic data show that NPIs are valid approaches in chronic disease treatments on par with allopathic therapies regarding goals and risks. These approaches have proven superior to some conventional treatments because they tend not to cause such severe side effects.

It might be interesting to look at the quantitative and qualitative changes resulting from single interventions or combining non-pharmacological interventions to further test their efficacy and safety, as well as to improvise on existing therapeutic strategies to prevent or cure disease and disability.

Illustrated by various clinical situations, the objective of management is to seek synergy in the mechanisms of action of treatments to improve quality of life, reduce the need for xenobiotics, and consequently the side effects participating in vicious circles chronicity.

The current imperative is to determine what works best under what conditions.

Multiple medical problems often face limited treatment options, the increased risk of adverse effects, complex drug interactions, and the concurrent use of multiple medications.

From our current perspective, the potential benefit of including nutrition in personalizing pain medicine is formidable and highly promising. The role of personalized nutrition and nutraceuticals, by considering how they might be helpful in managing chronic pain, as well as their physiological features (such as body mass and microbiome) and pathological ones.

The need for a multidisciplinary evaluation and treatment focusing on drug metabolism and chronobiology is highlighted. This multimodal approach influences pain via synergistic non-drug associations like pharmaco-nutritional, acupuncture, neuro-acupuncture, and PEA. Acupuncture in this multidisciplinary model is a multimodal pain regulator. The therapeutic and post-effect are augmented by cellular physiological rehabilitation.

#### **Conflict of interest**

No conflict of interest to declare.

#### **Abbreviations**

*Combining Modern Pharmacology with Integrative Medicine: A Biopsychosocial Model… DOI: http://dx.doi.org/10.5772/intechopen.112906*

#### **Appendix**

The philosophy behind the score sheets states that individuals or groups define a standard for the quality of their performance. Then, they describe the standard in terms of a set of requirements. This set is the score sheet. It allows for peer evaluation and selfevaluation of an activity. Grading proceeds by determining the fraction of requirements fulfilled and is objective and reproducible. The score sheet exists prior to the execution of any activity and thus induces iteration until the performance becomes satisfactory. Any individual or group can adapt the method to any professional activity by selecting the pertinent requirements to fulfill their standard of excellence.

#### **Author details**

Agnes Mazic De Sonis Pain Medicine Pole Neuroscience, Chirec Delta Hospital, Brussels, Belgium

\*Address all correspondence to<EMAIL_ADDRESS>
© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Tick H et al. Evidence-based nonpharmacologic strategies for comprehensive pain care: The consortium pain task force white paper. Explore (New York, N.Y.). 2018;**14**(3):177-211

[2] Hay JL et al. Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients. The Journal of Pain. 2009;**10**(3):316-322

[3] Junien C. Early determinants of health and disease: Epigenetics and environment. Bulletin de L'academie Nationale de Medecine. Mar 2011; **195**(3):511-526; discussion 526-527. DOI: 10.1016/s0001-4079(19)32060-6. PMID: 22292301

[4] Kanherkar RR, Bhatia-Dey N, Csoka AB. Epigenetics across the human lifespan. Frontiers in Cell and Development Biology. 2014;**2**:49

[5] Mazic-de Sonis A. Multimodal management of chronic pain: Litterature on the basic research and clinical expertise. In: 14 Congrès National de la SFETD. Lyon, France: La Société Française d'Études et de Traitement de la Douleur; 2014

[6] Plaghki L. Update on nociceptors. In: Quarterly Meeting October. Liège: GRID; 2014

[7] Akbarali HI, Dewey WL. The gutbrain interaction in opioid tolerance. Current Opinion in Pharmacology. 2017;**37**:126-130

[8] Meng J et al. Morphine induces bacterial translocation in mice by compromising intestinal barrier function in a TLR-dependent manner. PLoS One. 2013;**8**(1):e54040

[9] Trusheim MR, Berndt ER. Economic challenges and possible policy actions to advance stratified medicine. Personalized Medicine. 2012;**9**(4):413-427

[10] Ozdemir V et al. Mapping translational research in personalized therapeutics: From molecular markers to health policy. Pharmacogenomics. 2007;**8**(2):177-185

[11] Arar N et al. The genome-based knowledge management in cycles model: A complex adaptive systems framework for implementation of genomic applications. Personalized Medicine. 2011;**8**(2):191-205

[12] Sandberg M et al. Different patterns of blood flow response in the trapezius muscle following needle stimulation (acupuncture) between healthy subjects and patients with fibromyalgia and workrelated trapezius myalgia. European Journal of Pain. 2005;**9**(5):497-510

[13] Shinbara H et al. Participation of calcitonin gene related peptide released via axon reflex in the local increase in muscle blood flow following manual acupuncture. Acupuncture in Medicine. 2013;**31**(1):81-87

[14] Carlton SM. Nociceptive primary afferents: They have a mind of their own. The Journal of Physiology. 2014;**592**(16):3403-3411

[15] Pan WX. Bidirectional regulation of acupuncture and its plausible mechanisms. Zhen Ci Yan Jiu. 2019;**44**(11):843-853

[16] Dinan TG et al. Collective unconscious: How gut microbes shape human behavior. Journal of Psychiatric Research. 2015;**63**:1-9

*Combining Modern Pharmacology with Integrative Medicine: A Biopsychosocial Model… DOI: http://dx.doi.org/10.5772/intechopen.112906*

[17] Harris RE et al. Traditional Chinese acupuncture and placebo (sham) acupuncture are differentiated by their effects on mu-opioid receptors (MORs). NeuroImage. 2009;**47**(3):1077-1085

[18] Napadow V et al. Brain correlates of phasic autonomic response to acupuncture stimulation: An eventrelated fMRI study. Human Brain Mapping. 2013;**34**(10):2592-2606

[19] De Gregori M et al. Combining pain therapy with lifestyle: The role of personalized nutrition and nutritional supplements according to the SIMPAR Feed Your Destiny approach. Journal of Pain Research. 2016;**9**:1179-1189

[20] Rea K, Dinan TG, Cryan JF. The microbiome: A key regulator of stress and neuroinflammation. Neurobiol Stress. 2016;**4**:23-33

[21] IASP. Integrative pain medicine: A holistic model of care. IASP: Pain Clinical Update. 2014;**22**:1-6

[22] Ticinesi A et al. Gut microbiota composition is associated with polypharmacy in elderly hospitalized patients. Scientific Reports. 2017;**7**(1):11102

[23] Burneo JG et al. Weight loss associated with vagus nerve stimulation. Neurology. 2002;**59**(3):463-464

[24] Cork SC et al. Extracellular pH monitoring for use in closed-loop vagus nerve stimulation. Journal of Neural Engineering. 2018;**15**(1):016001

[25] Ikramuddin S et al. Effect of reversible intermittent intra-abdominal vagal nerve blockade on morbid obesity: the ReCharge randomized clinical trial. JAMA. 2014;**312**(9):915-922

[26] Shikora S et al. Vagal blocking improves glycemic control and elevated blood pressure in obese subjects with type 2 diabetes mellitus. Journal of Obesity. 2013;**2013**:245683

[27] Pardo JV et al. Weight loss during chronic, cervical vagus nerve stimulation in depressed patients with obesity: An observation. International Journal of Obesity. 2007;**31**(11):1756-1759

[28] Hu X et al. PLGA-curcumin attenuates opioid-induced hyperalgesia and inhibits spinal CaMKIIα. PLoS One. 2016;**11**(1):e0146393

[29] Teiten MH, Dicato M, Diederich M. Curcumin as a regulator of epigenetic events. Molecular Nutrition & Food Research. 2013;**57**(9):1619-1629

[30] Anand P et al. Bioavailability of curcumin: Problems and promises. Molecular Pharmaceutics. 2007;**4**(6):807-818

[31] Nau R et al. Strategies to increase the activity of microglia as efficient protectors of the brain against infections. Frontiers in Cellular Neuroscience. 2014;**8**:138

[32] Hesselink JM, Kopsky DJ. Enhancing acupuncture by low dose naltrexone. Acupuncture in Medicine. 2011;**29**(2):127-130

[33] Toljan K, Vrooman B. Low-dose naltrexone (LDN)-review of therapeutic utilization. Medical Sciences. 2018;**6**(4):82

[34] Zylicz Z, Stork N, Krajnik M. Severe pruritus of cholestasis in disseminated cancer: Developing a rational treatment strategy. A case report. Journal of Pain and Symptom Management. 2005;**29**(1):100-103

[35] Chindalore VL et al. Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia: A randomized, controlled trial of Oxytrex. The Journal of Pain. 2005;**6**(6):392-399

[36] Webster LR et al. Oxytrex minimizes physical dependence while providing effective analgesia: A randomized controlled trial in low back pain. The Journal of Pain. 2006;**7**(12):937-946

[37] Movafegh A et al. An ultra-low dose of naloxone added to lidocaine or lidocaine-fentanyl mixture prolongs axillary brachial plexus blockade. Anesthesia and Analgesia. 2009;**109**(5):1679-1683

[38] Hay JL et al. Potentiation of buprenorphine antinociception with ultra-low dose naltrexone in healthy subjects. European Journal of Pain. 2011;**15**(3):293-298

[39] Xiao Y et al. A randomized clinical trial of the effects of ultra-low-dose naloxone infusion on postoperative opioid requirements and recovery. Acta Anaesthesiologica Scandinavica. 2015;**59**(9):1194-1203

[40] Firouzian A et al. Ultra-low-dose naloxone as an adjuvant to patient controlled analgesia (PCA) with morphine for postoperative pain relief following lumber discectomy: A doubleblind, randomized, placebo-controlled trial. Journal of Neurosurgical Anesthesiology. 2018;**30**(1):26-31

[41] Gironi M et al. A pilot trial of lowdose naltrexone in primary progressive multiple sclerosis. Multiple Sclerosis. 2008;**14**(8):1076-1083

[42] Cree BA, Kornyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Annals of Neurology. 2010;**68**(2):145-150 [43] Turel AP et al. Low dose naltrexone for treatment of multiple sclerosis: A retrospective chart review of safety and tolerability. Journal of Clinical Psychopharmacology. 2015;**35**(5):609-611

[44] Ludwig MD et al. Long-term treatment with low dose naltrexone maintains stable health in patients with multiple sclerosis. Multiple Sclerosis Journal—Experimental, Translational and Clinical. 2016;**2**:2055217316672242

[45] Raknes G, Småbrekke L. Low dose naltrexone in multiple sclerosis: Effects on medication use. A quasi-experimental study. PLoS One. 2017;**12**(11):e0187423

[46] Black N. Why we need observational studies to evaluate the effectiveness of health care. BMJ. 1996;**312**(7040):1215-1218

[47] Philips Z et al. Review of guidelines for good practice in decision-analytic modelling in health technology assessment. Health Technology Assessment. 2004;**8**(36):iii-iv, ix-xi, 1-158

## *Edited by Theodoros Aslanidis and Christos Nouris*

With more than 230 million surgical procedures performed annually worldwide, and 30% or more of people affected by chronic pain globally, pain management is consistently a top priority. Its personal and social burden is enormous and thus much literature and research focuses on pain medicine. Along with the evolution of precision medicine, today's typical pain management strategies include a personalized, multimodal, interdisciplinary treatment approach, which might include pharmacotherapy, psychotherapy, integrative treatments, and invasive procedures. This book presents the latest advancements in pain management, covering a wide field of topics in pain medicine.

*Rosario Pignatello, Pharmaceutical Science Series Editor*

Published in London, UK © 2024 IntechOpen © LucaDAddezio / iStock

Pain Management - From Acute to Chronic and Beyond

IntechOpen Series

Pharmaceutical Science, Volume 1

Pain Management

From Acute to Chronic and Beyond

*Edited by Theodoros Aslanidis and Christos Nouris*


**7.4 Intradural steps**

The dura mater is opened in a curvilinear fashion and the intradural portion of the tumor is progressively resected using conventional microsurgical methods, alternating debulking and peripheral dissection from the brain parenchyma and vessels. An additional dural incision directed medially toward the optic canal may cautiously be performed to complete the extradural anterior clinoidectomy. Once the optic canal has been widely opened intradurally (**Figure 5**), the tumor fragments at this level can be easily removed using a small blunt hook.

Complete resection is not always possible due to true intracavernous invasion (as opposed to a simple extension to the lateral wall) or excessive tumor adherence in the SOF or optic canal. In such situations, the key is to optimally decompress the ON so that the residual tumor can later be effectively treated with radiation therapy. The radiosensitivity of the ON justifies the creation of a safety zone around it, in order to avoid deleterious iatrogenic irradiation during radiation treatment. It is essential to preserve the function of the cranial nerves as much as possible, as their postoperative recovery is often uncertain.

### **7.5 Closure and reconstruction**

If the ethmoidal or sphenoidal sinuses are open during the extradural steps, either autologous fat or a temporal muscle graft should be harvested to plug the defect, depending on the size of the opening (for example, the muscle should be used for a small aperture of a pneumatized ACP and fat should be used for a large sinus opening secondary to intranasal tumor invasion). A synthetic fibrin sealant may be used in addition to these measures to prevent postoperative cerebrospinal fluid leakage. The dural and periorbital defects are ideally managed using a vascularized and pedicled pericranial graft that is rotated over the orbit. Alternative solutions include using the temporal fascia or synthetic dura patches.

Bone reconstruction for SOM is often more complex than for other meningiomas due to the extensive bony resection, which sometimes involves the superior and lateral orbital rims. Various options are available to perform cranioplasty and obtain a satisfactory cosmetic result. If the orbital margins are intact, the healthy part of the craniotomy can be replaced using grids that are cut to a suitable shape and serve as anchor points for the reinsertion of the temporal muscle. For larger defects, hydroxyapatite cement can be shaped easily. A custom-made polymethylmethacrylate or polyetheretherketone (PEEK) prosthesis can be ordered before the procedure, especially when the orbital rims are planned to be resected. The design of the prosthesis can also compensate for temporal muscle atrophy by incorporating an increased thickening at the level of the temporal fossa. Trimming of the edges of the prosthesis is often required to perfectly match the craniotomy. The zygomatic osteotomy must be reattached with standard plates before reinserting the temporal muscle and suturing the scalp in layers according to the usual technique.

### **8. Complications and postoperative care**

The first postoperative night is ideally spent in an intensive care unit, so that the patient can be closely monitored, and any respiratory, hemodynamic, or neurological failures can be detected at an early stage, particularly in the event of a surgical site hematoma. Most postoperative complications of SOM are related to the cranial nerves affected by the tumor. In their meta-analysis of retrospective series of operated SOM, Fisher *et al.* summarized the incidence of occurrence of these complications [12]. Ophthalmoplegia was frequent (16%) and mainly related to oculomotor nerves damage (oculomotor III 11%; trochlear IV 2%; abducens VI 6%; not specified 13%). In addition, ptosis or diplopia (neuropathic or restrictive) was observed in 17% of cases each. Regarding the optic nerve, visual field loss was described in 4% of cases, while visual acuity was decreased in 9%, and blindness was reported in 3% of cases. Trigeminal hypoesthesia was the most frequent complication (19%); in contrast, facial paralysis was rare (4%). Regarding complications related to the brain, the incidence of epilepsy was estimated to be 8%, while motor and phasic

#### *Spheno-Orbital Meningiomas DOI: http://dx.doi.org/10.5772/intechopen.101983*

deficits, or diabetes insipidus were uncommon. Enophthalmos and cerebrospinal fluid leaks were encountered in 5% of cases each. Meningitis occurred in 7% and wound infections occurred in 3% of cases, which is consistent with the general rate of infection in cranial surgery, which was reported to be 9% [27]. Finally, pulmonary embolism was diagnosed in 4% of the patients who underwent an operation for SOM.


*4.3. Analysis of the Variation Characteristics of Kernel Density in Dingzhou*

A kernel density analysis of rural settlements in Dingzhou can be used to understand their agglomeration in space and time. We used the kernel density analysis tool in Arc GIS software to examine rural settlements in Dingzhou from 1962 to 2020.The results of the kernel density analysis show (Figure 7) that the maximum kernel densities of rural settlements in Dingzhou from 1962 to 2020 were 0.998 km2, 0.996 km2, 0.919 km2, 0.983 km2, 1.162 km2, and 1.149 km2. The scale and distribution density of rural settlements in Dingzhou are generally increasing overall. In 1962 and 1972, the high density values of rural settlements were concentrated in the areas surrounding towns and along rivers, such as Kaiyuan Town, Qingfeng Dian Town, and Gaopeng Town, and rural settlements far from urban areas and river areas were scattered. In the 1980s, the kernel density values in the surrounding areas of towns and along the river decreased, and high density values appeared in Zhuanlu Town. In 2000, compared to the original trend, the density values of rural settlements in Dongliu Chun Town and Xicheng Town increased. The spatial distribution of the kernel density values in 2010 and 2020 was basically the same, and the density values of rural settlements in the surrounding areas of cities and towns increased. Except for the high-value agglomeration in the surrounding areas of towns, areas demonstrated a new trend of multicore fragmentation based on the original trend.

From a local point of view, from 1962 to 2020, the high kernel density values were mainly distributed in parts of the central, western, and southeastern parts of Dingzhou City, and there were also cases where the kernel density values decreased in these areas. Based on an analysis of the number and spatial characteristics of rural settlements in the study area, we learned that the total area of rural settlements in the study area is increasing year by year, and there are merging rural settlements. Some rural settlements retreated to cultivated land, and existing settlements continued to expand, gradually connecting and merging with surrounding settlements. These changes resulted in a decrease in the kernel density value of some areas.

#### **5. Discussion**

#### *5.1. Main Policies Affecting the Changes of Rural Settlements and Stages*

In rural areas of China, the policy for homesteads (land for building rural housing, the main component of rural settlements) profoundly affects rural settlements. The homestead system is an important part of China's land system. It began during the founding of the People's Republic of China. Continuous adjustment and improvement meant that it was relatively complete and gradually standardised in the late 1980s. We divided the policies causing changes in the spatial pattern of rural settlements in Dingzhou into five periods (Figure 8): the period of transition from "private ownership of farmers" to "one homestead, two systems", the period of the "unified planning" of homesteads, the period of the "paid use" of homesteads, the period of "connecting increase and decrease" in homesteads, and the period of "separation of three rights" of homesteads.

**Figure 8.** Partial Homestead Policy 1949–2020. Note: I: the period of transition from "private ownership of farmers" to "one homestead, two systems" (1949–1972) [47–51]; II: the period of "unified planning" of homesteads (1972–1990) [52–56]; III: the period of "paid use" of homesteads (1990–2000) [57–61]; IV: the period of "connecting increase and decrease" of homesteads (2000–2010) [62–66]; V: the period of "separation of three rights" of homesteads (2010–2020) [67–71].

5.1.1. 1949–1972: Period of Transition from "Private Ownership of Farmers" to "One Homestead, Two Systems"

The Common Program of the Chinese People's Political Consultative Conference adopted in 1949 [47] proposed that farmers' land ownership should be protected and that land (including homesteads) should be distributed to farmers free of charge. After the founding of the People's Republic of China, China reformed the rural land system. The Land Reform Law of the People's Republic of China [48] promulgated in 1950 proposed the establishment of a privately owned land system by farmers. In 1955, the Draft of the Pattern Constitution of Agricultural Production Cooperatives [49] stated that means of subsistence were privately owned and that means of production should be gradually nationalised. At this time, as a general rule, farmers were self-employed, and homesteads were distributed evenly and could be obtained free of charge. In 1962, the [46] established the principle of "one homestead, two systems" (that is, a homestead occupied by farmers for building houses are collectively owned, and the houses built on the homestead are owned by farmers individually) rural homestead pattern. Homesteads were transformed from peasant ownership to rural collective ownership. In 1963, the Circular of the Central Committee of the Communist Party of China on Making Some Supplementary Regulations on the Issue of Homesteads for Members [50] first proposed the concept of the right to use homesteads. During the period when the private ownership of peasants changed to "one homestead, two systems", the original ownership of homesteads was changed to a right to use the homestead, beginning the era of the "separation of two rights" of homesteads [51]. At this time, the framework of China's homestead system was preliminarily formed. As the concept of the right to use homesteads gradually became clear, the total number of homesteads remained stable.


# **Food Processing and Its Impact on Phenolic and other Bioactive Constituents in Food**

Edited by Jan Oszmianski and Sabina Lachowicz-Wiśniewska Printed Edition of the Special Issue Published in *Molecules*

www.mdpi.com/journal/molecules


**4.2. Chinese medicines and their active compounds for inducing liver cancer cells differentiation**

Panaxydol is one of the bioactive components in Panax Notoginseng (Sanqi in TCM). Panax Notoginseng is a famous hemostatic in TCM and it can also relieve other blood disorders, such as blood stasis or blood deficiency. Recent studies have shown that the panaxydol could induce cell differentiation in human HCC cell lines SMMC‐7721 [36]. Ultrastructure morphology observation confirmed that there have obvious cell morphologic changes after panaxydol treatment. The activity of several differentiation related proteins such as alkaline phosphatase and albumin were increased, while AFP activity was significantly decreased after panaxydol treatment. These results showed that panaxydol may be a potential antihepatoma agent by inducing tumor cell differentiation.

Gepsin can also inhibit liver cancer development by inducing cancer cells differentiation. Studies showed that after gepsin treatment, the HCC cell line Bel‐7402 presents ultrastructural morphology of differentiation. Western blot results revealed that the differentiation related proteins such as the AFP protein secretion significantly decreased, while ALB protein expres‐ sion was obviously up‐regulated on gepsin‐treated cancer cells [34].

Ginseng is one of the most widely used herbs in TCM for thousands of years. Ginsenosides are the main bio‐active components in Ginseng. There are many reports verified the anticancer effect of ginsenosides *in vitro* and *in vivo*. For example, ginsenosides‐Rh2 (G‐Rh2) can inhibit the proliferation of SMMC‐7721 cells as well as induce the mature and normality of cell ultrastructure morphology. The expression of AFP, gamma‐GT and heat‐resistant ALP were also significantly decreased after 10 mg/ml G‐Rh2 treatment [37].


membrane contactor, with a focus on the recovery of dissolved methane. The studies reviewed showed that dissolved methane recovery using a degassing membrane contactor was higher under the following conditions: low liquid velocity or flux, higher transmembrane pressure, use of porous or micro-porous membrane, flow of liquid from the lumen side of the membrane, presence of carbon dioxide desorption, longer retention time, and low temperature. Moreover, the highest reported recovery of dissolved methane from an AnMBR effluent was around 99% obtained using a polypropylene micro-porous membrane with a liquid velocity of 0.0004 m/s. Therefore, further studies with an aim to optimize recovery and development of new membranes, while considering membrane fouling and pore wetting problem. Finally, this optimization should consider the economy of the system as well.

## AUTHOR CONTRIBUTIONS

PV synthesized the whole review paper, as part of her on-going doctorate study. This was then reviewed and edited by VJ and MO.

## FUNDING

This review is part of the on-going doctorate study of the first author under the grant from the Commission on Higher Education, Philippines, the University of the Philippines, and the RMIT University, Australia.

#### ACKNOWLEDGMENTS

The authors would like to acknowledge RMIT University, Australia and the government of the Philippines for the academic and financial support.

and potential for recovery as an energy product: a review. Water Res. 104, 520–531. doi: 10.1016/j.watres.2016.08.019

Technologies for Sustainable Water Management (Reston: ASCE Library), 867–901. doi: 10.1061/9780784414422.ch25

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2018 Velasco, Jegatheesan and Othman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.


**Author details**

Rodrigo Teixeira Bento and Marina Fuser Pillis\*

\*Address all correspondence to<EMAIL_ADDRESS>
Materials Science and Technology Center, Nuclear and Energy Research Institute (CCTM-IPEN/CNEN), Cidade Universitária, São Paulo, Brazil


2.2.14. Statistical Analysis

The statistical analysis of the data was carried out using GraphPad Prism ® for Windows, version 5.01, applying a Student's *t*-test or one-way ANOVA with Tukey's post-test with 95% of confidence when appropriate. Statistical significance was when *p* < 0.05.


**2.1 Mortars as composite materials**

Composites are materials made by combining two or more other materials. These materials are important in the construction sector as building technology has been favored by the advanced properties that composites can offer. The development of composite materials along with related design and manufacturing technologies constitute one of the most important advances in the history of materials. Composites are multifunctional materials having unprecedented mechanical and physical properties that can be tailored to meet the requirements of a particular application [19]. Thus, new achievements have been constructed as the innovative composites could add new possibilities to the engineers' imagination.

Mortars are a specific type of composite material, which consists mainly of three phases—paste as the matrix, interface transition zone (ITZ), and aggregates. The properties of mortars are influenced by:

At fresh state, mortar should be workable (do not break and do not flow), plastic (to have consistency to hold and not flow on overload loads) and it should show volume stability (do not cause contractions or expansions). At harden state, it should have the required strength and the required porosity. Aggregates constitute the strongest phase, hold a significant percentage in the volume of mortar and are frequently used in sand size (up to 4 mm). Conditions for the use of aggregates in mortars is the health of both the parent rock and the grains (without breaks, cracks, impurities), low porosity—small absorption index, homogeneous granulometric grade, percentage of the fines (<0.075 mm) should not exceed 5% [20]. The presence of fines in lime-based mortars can cause considerable alterations to the properties of the mortars. Their presence significantly reduces the strength and increases the volume shrinkage of mortars [21]. Furthermore, the porosity can be increased, and the same can also happen with capillarity when fine aggregates are participating in excess. Additionally, the type of fines also seems to play a role in their behavior in relation to the basic binder. For example, the strength is decreased in compositions with clay fines while porosity is affected mainly by limestone fines [22]. Capillarity also seems to be affected by the type of fines as the compositions containing fines 10–15% presented low absorption probably because fines block capillary pores [23].

In the case of mortars, as composite materials and keeping in mind that aggregates retain the inherent properties of the rocks from which they are derived, it can explain that the color, the chemical and physical characteristics of the aggregates directly affect the specific weight, the measure of elasticity, the volume stability, the appearance, and the mechanical and physical properties of mortars. The addition of sand to a binding system in mortars technology has proved to confer technical advantages as they contribute to volume stability, durability, and structural performance [16]. The gradation of the aggregates was wide, but the most adequate part was sand of 0–4 mm. Coarse aggregates up to 1 cm were used in thick joints [10] and also combined with sand for structural mortars while sand or finer aggregates (0–2 mm) are usually the constituents of the renders or plasters [24]. Usually, aggregates are obtained after the gentle grinding and sieving (based on EN1015-1) [25]. Even homogeneous distribution of grains is usually obtained as shown in **Figure 2** in a typical bedding mortar.

The ratio of binder to aggregates (B/A) ranges widely but it could be said that for most of the structural mortars, it is 1:2.5 or 1:3 while for the renders and plasters are

**Figure 2.** *Typical gradation of old structural mortar.*

#### *The Role of Sand in Mortar's Properties DOI: http://dx.doi.org/10.5772/intechopen.102489*

richer in binder content and the ratio is mostly 1:1 or 1:1.5 [23]. Apart from the different types of aggregates, as their mineralogy and origin are concerned, the volume content in the mixture, the maximum size, and their gradation influences the structure of a binder—aggregate mixture and the performance of mortars overall [10]. The added aggregates strengthen the composite, and the associated interface weakens it. These two opposite effects offset each other, and the combination of them leads to declined strength. Generally, a strong cohesion between the mortar binder and coarse aggregate confirms the good masonry properties. On the other hand, the increase of aggregate content reduces the workability of a mix and thus, reduces the strength as well [26]. It has been mentioned before that aggregate plays a role in restraining the shrinkage of cement paste, and that the shrinkage of the aggregate itself can be neglected [27]. It has been found in various composite materials that a certain amount and proper size of the aggregate are beneficial to the strength and fracture energy of the composite [28]. For mortar specimens, aggregates have a significant influence on both rheological and mechanical properties. Their specific gravity, particle size distribution, shape, and surface texture influence markedly the properties of mortars in the fresh state. On the other hand, the mineralogical composition, toughness, elastic modulus, and degree of alteration of aggregates are generally found to affect the properties of mortars and in the hardened state [29]. The drying shrinkage strains in investigated mortars are changed significantly by different kinds of fine aggregate materials. The water content of the mortar mix proportion is a major factor in drying shrinkage evolution. Increasing the unit water content can result in an increase in the amount of capillary water, and hence more shrinkage strain would be obtained. The bonding stress of the weak interface zone between the coarse aggregate and paste can be improved when a chemical reaction between the aggregates and the paste [30].

More recently, the role of the recycled sand from waste demolition, when examined in mortars, revealed that it was more beneficial in lime mortars rather than in stronger lime-pozzolan or lime-pozzolan and cement mortars as a decrease in their performance were recorded in the latter cases due to the mortars' structure [31]. It seems that two competitive mechanisms acted in these mortars; high porosity (due to high water content and the nature of the aggregates) which assists toward low strength and durability and the chemical reaction due to the presence of reactive components which creates a strong structure. This chemical reaction is a stronger mechanism in the case of lime mortars and prevails in relation to the competitive mechanisms of the higher porosity [32].

In an effort to test different aggregate-related properties to hydraulic lime mortar, Pavia et al. suggested [33] that an increase in the calcite content of the aggregate lowers the flexural and compressive strength of the mortar. At the same time, they proved that sharp aggregate, as well as aggregate with small average particle size, tends to increase the mechanical strength and bulk density of a mortar simultaneously reducing porosity, water absorption, and capillary suction. Additionally, they concluded that aggregates containing particles of a wide size range can increase the mechanical strength and bulk density of the hardened mortar diminishing porosity, water absorption, and capillary suction.

#### **2.2 Different sands in mortars**

The role of aggregates on the structure and behavior of lime-based mortars is examined by studying the influence of the aggregate content, type, and grain size on the strength, porosity, and volume stability of the mortars. Trying to understand how

**Figure 3.** *(a) Black sand, (b) yellow sand, and (c) blonde sand.*

the properties of the sands influence important macroscopic properties of pure lime mortar, threes sands that were available in the market were selected and analyzed in the laboratory. All of them were river origins of siliceous content (**Figure 3**).

X-ray diffraction analysis (XRD) using a D2 Phaser 2nd generation, Bruker instruments, indicated that blonde sand was containing quartz, feldspar, magnetite, calcite, hornblende. Yellow sand contained quartz, feldspar, magnetite and black contained quartz, feldspars, biotite, and hornblende. Physical properties, such as water absorption, specific gravity, and sand equivalent (S.E.), are shown in **Table 1** while the chemical analysis revealed the silicic nature of the sands (**Table 2**).

Lime mortars were prepared using lime CL90 (based on EN459) [34] and the compositions were produced, as shown in **Table 3**. The workability was measured with a flow table as described in EN1015-3 [35].

The samples were cured based on EN456 and at 28 days, the compressive strength and the open porosity were recorded (**Table 4**).

The results show that there are different properties recorded in the produced mortars even when siliceous sands are used. The different properties, such as S.E. and the

#### **Table 1.**

*Physical properties of sands.*

**Table 2.** *Chemical analysis of sands.*

*The Role of Sand in Mortar's Properties DOI: http://dx.doi.org/10.5772/intechopen.102489*

#### **Table 3.**

*Composition of trial mortar mixtures.*

#### **Table 4.**

*Properties of the produced mortars at 28 days.*

water absorption capacity of the sand grains, influence both the fresh (workability) and the hardened properties (porosity, strength) of the produced mortars.

The natural sands can be of similar origin with the crushed but weathering not only rounded the particles but also changed the proportions and removed most of the light minerals, such as the flaky micas. Due to these differences, mixtures with crushed sand often display higher water demand and lower workability than the corresponding composite with glaciofluvial sand. Additionally, crushed sand has a positive impact on long-term strength. It seems that, when rough-grained sand is used, strong cohesion with the binder can be achieved, as shown in **Figure 4**, where mortars with rounded and crushed sand were examined under scanning electron microscopy (SEM) [17].

The mechanical features, particle shape, grading, and physical properties, such as moisture absorption, sand equivalent value, are what can be labeled as properties of interest in the aggregates when used in mortars. Some of these most important properties are shown in **Table 5**.

#### **Figure 4.**

*SEM examination of rounded sand grain (left) where there is a gap in the contact zone and angular grain with strong cohesion (right).*

#### **Table 5.**

*Important properties of aggregates to be used in mortar production.*

The bond behavior in the interface between the binder and the aggregates has a strong effect on the mortar properties since the effectiveness of the reinforcement provided by the addition of particles depends on the interfacial bond (**Figure 5**). This is since the size, shape, and content of the particles predominantly control the morphological features of the internal structure of the composite.

The test results showed that with increasing volume fraction of aggregate, the compressive strength of the composite decreases, which is different from the prediction of conventional composite theories. The possible explanation of this result is

#### **Figure 5.**

*Macroscopic examination of contact zones of natural aggregates and binders in old mortars. Despite the presence of cracks in the binder in the left image, the cohesion is strong. On the right, there are pores on the interface probably due to the high content in aggregates in relation to the binder.*

**Figure 6.**

*Examination under SEM of natural aggregate and lime binder with weak ITZ (left) and crushed brick as aggregate and lime-pozzolan binder with strong ITZ (right).*

based on the interface transition zone (ITZ) around the aggregate, which is the weak zone in composites (**Figure 6**) [15]. With more aggregate added into the mixtures, more interfaces are formed in the hardened material. The compatibility between the aggregate of the paste affects the development of strong cohesion at the aggregatematrix interface in many cases and that usually indicates the good performance of the mortar. As aggregates are, by weight or by volume, the major component of mortars, they can be a source of silica, which can react in certain conditions with the binder, leading to the formation of reaction rims at the edge of the grains and recrystallization along with the pre-existing cracks (**Figure 7**).

Apart from the different types of aggregates as their mineralogy is concerned, the volume content in the mixture, the maximum size, and their gradation influences the structure of a binder—aggregate mixture [3, 5]. The analysis of mortars reveals that higher strength values are attained for lime mortars of low binder/aggregate (B/A) ratio (1:1.5, 1:2.5, and 1:3) which contained sand (0–4 mm). Coarse aggregates have

#### **Figure 7.**

*Old mortars under the polarized microscope (x10). Reaction rim in the interfacial zone of the binders and the aggregates used.*

#### **Figure 8.**

*Pores and cracks in the structure of lime mortar with coarse aggregates (polarized microscope, x15).*

**Figure 9.** *Cracks inside the binder where they meet the aggregate volume as the obstacle.*

contributed positively to the volume stability of lime mortars. The microstructure has recorded the restriction of volume changes in cases where coarse aggregates have been used in the structure of lime mortars (**Figure 8**).

However, it is well recognized that coarse aggregate particles can act as crack arresters, as they restrict the shrinkage of the binder so that under an increasing load, extra energy is absorbed for the formation of a new crack (**Figure 9**) [36].


**4. Conclusions**

ZnO nanorods arrays with high surface area and well-aligned crystallographic orientation were produced via hydrothermal method. The annealed arrays exhibit a crystallite size of 45 nm with (002) preferred orientation and a relatively low lattice strain. Upon argon/SF6 plasma treatment for up to 20 min, the PL intensity in the orange/red region of ZnO is enhanced by 2-fold compared to the ZnO sample without plasma treatment. Moreover, the PL intensity in the blue spectral regime is almost suppressed due to increased defect density. For 5 min Ar/SF6 plasma treatment, the PL broad band intensity maximizes due to maximum oxygen content at the film surface. This finding implies presence of hydroxyl group at the surface, more oxygen in the ZnO lattice (*OL*), fluorine incorporation in terms of F–Zn and F–OH bonds, and passivation of the surface states as well as bulk defects. These findings have implications for fundamental studies and industrial application of the plasma modified ZnO nanostructures in optoelectronic applications including visible light emitting devices and display systems.

**Author Contributions:** A.A. and J.-J.P. designed the scheme of experiments; A.A., I.A., S.V. and K.S. performed the experimental work; M.I., J.-J.P. and G.D. carried out the data analysis; M.A.A. and S.V. accomplished data validation; M.I., A.A. and J.-J.P. prepared the original draft; G.D., M.A.A., I.A., S.V. and K.S. did the necessary writing review and editing; J.-J.P. and M.I. administered the project and acquired funding for this research.

**Funding:** The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding of this research through the Research Group Project no. RGP-283. The authors also express their gratitude to Wallonia Region for financial support (Project Cleanair; convention 1510618, compl. Feder films).

**Conflicts of Interest:** The authors declare no conflict of interest.


**Author details**

Clark D. Kensinger\* and Jon S. Odorico Department of General Surgery, Division of Transplant, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


*Article* **Competitive Detection of Volatile Compounds from Food Degradation by a Zinc Oxide Sensor**

**Lucio Bonaccorsi 1, Andrea Donato 1, Antonio Fotia 2,\*, Patrizia Frontera 1 and Andrea Gnisci 3**

Mediterranea University of Reggio Calabria, Via Graziella Loc. Feo di Vito, 89124 Reggio Calabria, Italy 3 Department of Heritage, Architecture, Urbanism (PAU), Mediterranea University of Reggio Calabria,

**Abstract:** During the phenomenon of food degradation, several volatile organic compounds are generally released. In particular, due to lipid oxidation in stored and packed meat, hexanal is formed as a typical decomposition product. Therefore, its detection can provide an important indication of the quality and conservation of meat. Unfortunately, the simultaneous release of other compounds, such as 1-pentanol and 1-octen-3-ol, during the first phase of the degradation process can have an undesirable effect on the detection of hexanal. In this work, a metal oxide (MOX) sensor based on zinc oxide (ZnO) was prepared and tested for possible use in the monitoring of low concentrations of hexanal. The sensor was expected to detect the target volatile with minimum interference from all the others, when released all at the same time. For this purpose, the ZnO sensor was exposed to both pure and different mixtures of vapors of the main competing organic compounds. Comparing the results of the mixtures to the response relating to pure hexanal, it was highlighted that the presence of 1-pentanol and 1-octen-3-ol decreases the response of the sensor to hexanal in terms of the eR/R0 ratio, especially at low concentrations (5–10 ppm), while at 50 ppm, the sensor response was comparable with the hexanal quantity, proving that its detection was less affected at higher concentrations.

**Keywords:** zinc oxide; gas sensor; hexanal; 1-pentanol; 1-octen-3-ol; MOX

#### **1. Introduction**

Food quality evaluation, shelf-life determination, and raw product control are important fields in which conductometric gas sensors have been applied in recent years. In these sensors, the gas detection mechanism is based on the conductance variation of a semiconducting metal oxide (MOX) layer caused by the chemical/physical adsorption of the gas molecules on the MOX surface [1]. MOX sensors have been intensively studied and used for their low production cost, reduced size, and high sensitivity to a broad range of chemicals. Compared to typical chemical analytical techniques used in food industry, the lower accuracy of MOX sensors is compensated by a faster response, higher portability for field usage, and less expansive instrumentation. A possible application of MOX sensors in the food industry for meat quality control is the detection of hexanal, a typical decomposition product of meat formed during lipid oxidation in stored and packed meat products [2–4]. Hexanal, indeed, is considered an important indicator of the freshness status [5,6] of raw meat products. In a preliminary work, we compared three different MOX sensors for hexanal detection and we found that zinc oxide (ZnO), used as the detecting layer for resistive sensors, showed the best compromise between the sensing temperature (T = 523 K) and response amplitude [7,8]. Indeed, the ZnO resistive gas sensor was tested with a broad range of hexanal concentrations in different working conditions, especially in

**Citation:** Bonaccorsi, L.; Donato, A.; Fotia, A.; Frontera, P.; Gnisci, A. Competitive Detection of Volatile Compounds from Food Degradation by a Zinc Oxide Sensor. *Appl. Sci.* **2022**, *12*, 2261. https://doi.org/ 10.3390/app12042261

Academic Editors: Alessandro Genovese and Johannes Schwank

Received: 30 November 2021 Accepted: 20 February 2022 Published: 21 February 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

terms of the working temperatures and relative humidity. However, although the suitability of the ZnO sensor for hexanal detection was proved, the influence of other factors needs to be considered. In particular, in real food monitoring conditions, the decomposition process leads to the formation of numerous volatiles even during the early stage and the sensor must have the ability to detect the target volatile with minimal interference from others. In other words, the sensor must show sensitivity and selectivity towards hexanal. In general, as known, selectivity is one of the major issues in conductometric sensors made of semiconductor oxides because the sensing mechanism based on the exchange of electrons on the sensor surface during the "oxidation" of the volatile molecules is not a selective process and similar compounds can oxidize at the same time [9]. Several alternatives to improve the selectivity and sensitivity of MOX sensors are under continuous development, for example, the synthesis of particular architectures, such as nanowires, nanotubes, and nanosheets [10], exploiting the effect of nanostructured materials with respect to the bulk form [11], or the preparation of conductometric sensors based on p/n-type heterojunctions [12]. Similarly, the development of electronic noses requires the implementation of different sensor arrays to improve the ability to discriminate between similar volatile compounds [9,13–15]. However, electron noses, which ensure the widest applicability, are complex and voluminous equipment that require trained specialists for their use. A single sensor or at most a combination of two makes the detection system easy to use even for unskilled operators and easily transportable, even if it is not usable for generic analyses but suitably developed for a specific application. From this point of view, a complete characterization of the sensor's behavior in the environment of interest is a fundamental step for the realization of the measurement system. Therefore, in this work, we studied the effect of the coexistence of the main volatiles formed during meat degradation on the response of a ZnO sensor to hexanal, which, to the best of our knowledge, has not been reported yet. In the first stage of the degradation process, 1-pentanol and 1-octen-3-ol are the two main compounds released together with hexanal that can unexpectedly and unwantedly interfere during the detection of the MOX sensor [4,6,16]. The ZnO sensor was initially exposed to the three pure compounds and subsequently to binary and ternary mixtures of the three compounds, simulating a degradation process, to compare the responses and evaluate the effect of the interference. The results showed that the interaction of the three volatiles on the ZnO surface interferes in the hexanal detection, reducing the sensor's sensitivity in comparison to the response to the vapors of the pure component. A comparative analysis of the transient response, however, showed that the electrical resistance of the ZnO sensor in the presence of hexanal vapors had a very rapid decrease that was not observed with the other compounds. Therefore, in a detection device based on a single ZnO sensor, the intensity of the signal, which is related to the vapor concentration, should not be the only parameter that is relied on, but the combination with the decrease rate of the sensor's resistance, which is distinctive of hexanal, has to be considered so to improve the reliability of the response.

#### **2. Experimental**

#### *2.1. Sensor Preparation and Characterization*

Zinc oxide powder was prepared dissolving zinc nitrate (0.68 M) in aqueous solution and hydrolyzing it with a solution of potassium carbonate (1 M) [8]. The precipitate was filtered, washed with deionized water, dried at 383 K for 12 h, and then calcinated at 673 K for 2 h in air.

The powder was characterized by XRD analysis, D2 Phaser, equipped with a heating chamber, Anton Paar HTK 1200N (Bruker, Billerica, MA, USA), in the 2θ range 15–65◦ (Cu Kα1 = 1.54056 Å) and by scanning electron microscopy (SEM) (Phenom ProX, Deben, Suffolk, UK). To evaluate the thermal stability of the synthesized zinc oxide, X-ray diffractometry at increasing temperatures was carried out to collect powder patterns at 298–373– 473–523–573–673 K.

The ZnO powder was mixed with ethanol in an ultrasonic bath. The alcoholic paste was painted, with a controlled thickness, on the surface of an alumina support (3 mm × 6 mm) with interdigitated Pt electrodes on one side and a Pt heater on the other. The sensor was annealed at 673 K for 2 h in air before the sensing tests to stabilize the microstructure of the film.

#### *2.2. Sensing Experiments*

Liquid solutions of the three compounds, hexanal > 98%, 1-pentanol > 99%, 1-octen-3-ol > 98% (Sigma Aldrich, St. Louis, MO, USA), were used to generate pure vapors and mixtures for the experiments.

For the detection tests, the sensor was placed in a stainless-steel cell and exposed to 100 sccm of the vapor mixture, consisting of dry air (the carrier) and organic compounds. Pure vapors were obtained by bubbling dry air in pure liquid organics maintained at 258 (±0.1) K by a refrigerated circulating bath. Different concentrations (5–10–50 ppm) of vapors were obtained by regulating air fluxes by a battery of mass flow controllers (Brooks Instruments, Hatfield, PA, USA). Similarly, binary and ternary mixtures of vapors were obtained by flowing dry air in liquid mixtures of compounds according to the composition reported in Table 1.

**Table 1.** The composition of liquid and vapor mixtures used in the sensing tests.

The gas concentrations of the pure compounds were calculated from the vapor pressures at T = 258 K estimated by the Antoine equation with coefficients from literature data [17–19]. The calculated values were compared with the evaporated quantities by periodically weighting the remaining liquid using an analytical balance. In the case of binary and ternary mixtures, the vapor concentrations were calculated using Raoult's law in the hypothesis of ideal mixtures:

$$\propto\_i P\_i^0 = y\_i P$$

where *xi* = molar fraction of the component *I* in the liquid mixture, *P*0 *i* = vapor pressure of the component *I*, *yi* = molar fraction of the component *I* in the gas mixture, and *P* = the total (atmospheric) pressure.

The sensor's resistance data were collected in the four-point mode by an Agilent 34970A multimeter while a dual-channel power supplier instrument, Agilent E3632A (Agilent Technologies, Santa Clara, CA, USA) allowed the sensor's temperature to be controlled, as explained elsewhere [7].

#### **3. Results**

#### *3.1. ZnO Characterization*

In Figure 1a, an SEM image of the synthesized ZnO powder is shown. The mean particle size of the powder ranged from 0.1–0.5 μm. The XRD pattern of ZnO acquired at 298 K is shown in Figure 1b and confirms the typical hexagonal structure of wurtzite (cell parameters: a = 3.249 Å, c = 5.207 Å) with crystallites size = 40.9 nm calculated by the Debye–Scherrer equation. MOX sensors, however, generally have a working temperature higher than 298 K. Thus, an investigation of the possible transformation/transitions of ZnO in temperatures ranging from 298–673 K was considered of interest, with T = 523 K being the working temperature of the sensor used in all the experiments and T = 673 K being the annealing temperature of the synthesized powder before the sensing tests. The results of the X-ray diffractometry and increasing temperature are shown in Figure 1b. After heating the oxide powder to 673 K, the hexagonal structure of ZnO did not show crystallographic variations as evidenced by the X-ray pattern and no increase in the peaks' intensity or variation in the peaks' shape were observed (Figure 1b), demonstrating that the particle size did not change at the annealing temperature. The only consequence of the powder heating was the shift in the diffractometric peaks towards lower angles when the temperature was increased, as shown in the inset of Figure 1b for the peak at 2-Tetha ≈ 31.7◦. This is an indication of the thermal expansion of the unit cell volume with the temperature. The thermal stability of the sensing layer is important because in the case of the sintering of oxide particles, the sensor response decreases with time [20–22]. SEM analysis of the ZnO powder after the annealing treatment at T = 673 K confirmed the previous result because no evidence of morphologic variations was observed (Figure 1a).

**Figure 1.** Electron microscopy (SEM) image of the ZnO powder as prepared at 298 K and after the annealing treatment at 673 K (**a**), X-ray patterns of ZnO from 298 K to 673 K and (inset) the temperature shift at 2θ = 31.7◦ (**b**).

#### *3.2. Sensing Experiments*

The sensor response was defined as the ratio of the reference resistance measured in dry air (R0) and the resistance when the sensor was exposed to the vapor mixtures (R). In all sensing experiments the sensor temperature was maintained at 523 K because this working condition resulted in the highest response in a previous study on the ZnO sensitivity to hexanal [8]. The first set of experiments was carried out by measuring the response of pure compounds to different concentrations in dry air, as reported in Table 2 and shown in Figure 2. The lowest concentration was set at 5 ppm (in dry air) because this is considered the threshold value for the perception of hexanal by the human nose and therefore is used as an indication of the onset of meat degradation processes [23,24].

**Table 2.** ZnO sensor's response to pure compounds (T = 523 K).

Comparing the data in Table 2, it is evident that ZnO is responsive to all three organic vapors, although in a different way. The sensor's response to hexanal, as already reported in a previous work in which the ZnO response to different hexanal concentrations was studied [8], is the highest up to C = 10 ppm. However, the response to 1-octen-3-ol shows the faster rise and exceeds all others at C = 50 ppm (Figure 2a). In contrast, the ZnO sensitivity for 1-pentanol is the lowest at all concentrations. The high sensitivity of ZnO to hexanal at 5 ppm and the growth rate of the signal with the concentration (in Figure 2b) indicate that the sensor's surface at C = 50 ppm of hexanal is close to the saturation of the adsorption centers so that the increase in the response is close to reaching an asymptotic value [22–24]. The response of the MOX sensor is the result of a complex interaction between the oxide surface and the adsorbed gas molecules so that the electrical properties of the ZnO layer are modified due to the effect of the redox reactions taking place with the adsorbed molecules and the oxygen ions on the layer surface [20,21,25–30]. The organic substances considered in our tests are chemically different with different reagent groups, which makes the comparison of the sensor response more difficult: hexanal is an alkyl aldehyde, 1-octen-3-ol is an unsaturated secondary alcohol, and 1-pentanol is an aliphatic alcohol. In these cases, the mechanism of reaction involves the preferential interaction of hexanal with the ZnO surface, which occurs through the carbonyl group of the aldehyde [5,7], while in the case of alcohols, the main interaction occurs through the hydroxyl group. Both aldehyde and alcohol compounds interact with oxygen ions on the sensor's surface by oxidation reactions of the respective functional groups. Another important property that can affect the interaction at the interface between a vapor and the sensor's surface is the volatility of the interacting substance.

**Figure 2.** (**a**) Comparison of the sensor's response to pure compounds according to data from Table 2 and (**b**) the transient response of the ZnO sensor to pure volatiles at 5 (**top**) and 50 ppm (**bottom**).

Table 3 shows the boiling temperatures and vapor pressures of the three pure compounds for a comparison with the observed sensor responses. Hexanal, as expected, is the chemical compound that showed the lowest boiling temperature and highest vapor pressure; however, the sensor showed a higher response to 1-octen-3-ol than 1-pentanol despite the higher Tb and lower vapor pressure shown by unsaturated alcohol (Figure 2a).

For a more complete characterization of the ZnO sensor, the transient responses corresponding to the data shown in Table 2 are shown in Figure 2b for 2 concentrations: 5 and 50 ppm, respectively. The electrical resistance of the ZnO layer decreases with time when exposed to the organic vapors (n-type behavior) as a consequence of the redox reactions

with the oxygen adsorbed on the sensor's surface and the consequent electron release into the conduction band of the semiconductor layer [7,20,31]. The transient response to hexanal compared to other volatiles was the fastest in the detection (R decrease), reaching the lowest resistance in seconds, and in regeneration in dry air (R increase) at all concentrations (Figure 2b). For the two alcohols, 1-pentanol and 1-octen-3-ol, the transient response was significantly slower than the hexanal response for both the detection and regeneration (Figure 2b). According to these results, although the value of the R0/R ratio is the reference parameter used for evaluating the sensor's sensitivity, the response as a function of time can be important for discriminating among competing species, such as in the examples shown. During the degradation process, however, the alcohol vapors are released simultaneously with hexanal so the sensor's response cannot be considered a simple addition of the responses to pure compounds.

**Table 3.** Boiling temperatures and vapor pressures of pure compounds.

To study the sensor's response in the presence of more than one volatile in the environment, a series of experiments were planned using binary and ternary mixtures. The results are shown in Table 4, where the composition of the vapor phases was determined as previously explained in the experimental paragraph.

**Table 4.** Sensor's response to binary and ternary mixtures.

According to [2,3,9,23,32], the beginning of food degradation is mainly correlated to the production of hexanal, which is predominant among the other organic compounds released and, indeed, is used as an indicator of the freshness of food and shelf-life determination. In our tests, this condition was simulated by binary mixtures with a concentration of 98/2 (w%). However, for a more complete characterization, the sensor was also tested with mixtures 75/25 (w%), with a higher concentration of the "competing" components (Table 4). Under the experimental conditions adopted, the vapors were generated by the liquid phase at T = 258 K and any reaction between the components was inhibited. The vapors were, then, conveyed directly to the sensor's surface, the temperature of which was maintained at 523 K. The sensing mechanism is mainly based on the oxidation reactions that are dominant on the sensor's surface, where, even in this case, due to the experimental conditions adopted, reactions between gas components are unlikely [33]. Indeed, the trend of the sensor's response and the stability of its working temperature confirmed the absence of side reactions due to the formation of intermediate compounds (such as acetal and hemiacetal) in the gas phase [33]. However, with respect to pure substances, different signals were registered when the binary and ternary mixtures were considered. Therefore, due to the complexity of the phenomena involved, which cannot only be described by a superposition of the signals from pure components, studying the sensor's response to binary and ternary mixtures was of fundamental importance. The sensor's response to hexanal/1-pentanol vapors compared to pure components is shown in Figure 3b. According to the data shown in Table 4, the sensor's behavior is strongly influenced by the presence

of alcohol, as also evident in the comparison shown in Figure 3a. When exposed to the mixture 98/2, the sensor was more sensitive to 1-penthanol at low concentrations (5 and 10 ppm) and only when the compounds' concentration increased to 50 ppm did hexanal detection become predominant (Figure 3a). In the presence of a higher concentration of 1-pentanol, mixture 75/25, the dominant effect of alcohol was confirmed as the detection of the hexanal was almost completely inhibited and the trend of the signal was similar to the case of the pure compound (Figure 3a). For a more complete characterization of the mixture 98/2, Figure 3b shows the sensor's resistance as a function of time at C = 5 and 50 ppm. At low concentrations, the transient response follows the 1-pentanol trend while at 50 ppm, the resistance's variation is similar to that of pure hexanal, in agreement with the results shown in Figure 3a. The sensor's response to hexanal was only evident at the highest concentration.

**Figure 3.** (**a**) Sensor's response to hexanal/1-pentanol mixtures (data from Table 4) and (**b**) transient response to mixture 98/2 (hexanal/1-pentanol) at 5 (**top**) and 50 ppm (**bottom**).

The effect of 1-octen-3-ol in combination with hexanal is shown in Figure 4 together with the response to the pure components. The ZnO sensor was significantly influenced by the presence of secondary unsaturated alcohol in both mixtures, 98/2 and 75/25, as evident from the data shown in Table 4 plotted in Figure 4a. The sensor signal, R0/R, is affected by the alcohol even in the mixture 98/2 at all concentrations, from 5 to 50 ppm (Figure 4a). At the highest concentration, the response was even more intense than the sum of the two signals. The transient response shown in Figure 4b confirms that the sensor is mainly influenced by the 1-octen-3-ol traces at all concentrations, although after increasing the concentration of the mixture 98/2 to C = 50 ppm, the sensor's resistance showed a decreasing rate regarding the detection, which is similar to the response to pure hexanal, which was much faster than in the presence of pure 1-octen-3-ol.

**Figure 4.** (**a**) Sensor's response to hexanal/1-octen-3-ol mixtures (data from Table 4) and (**b**) transient response to mixture 98/2 (hexanal/1-octen-3-ol mixtures) at 50 (**top**) and 50 ppm (**bottom**).

Finally, the ternary mixture with the composition 96/2/2 was used to study the ZnO sensor in an environment similar to the condition that develops when monitoring food degradation. Figure 5 shows the ZnO response to the different concentrations in dry air compared to the response recorded in the detection of hexanal vapors only.

**Figure 5.** (**a**) Sensor's response to the ternary mixture 96/2/2 (data from Table 4) and (**b**) the transient response of the ZnO sensor to the ternary mixture 96/2/2 for 5 (**top**) and 50 ppm (**bottom**).

Although the response increased with the concentration, the sensor was clearly negatively affected by the other two components of the mixture and low sensitivity was observed, especially at low concentrations. The comparison with the responses to the binary mixtures (Figure 5a) shows that the inhibition effect on the hexanal detection is mainly due to the presence of 1-pentanol vapors, which is the dominant component among the two alcohols.

A similar conclusion can be obtained from the analysis of the transient responses for the three mixtures tested, as shown in Figure 5b. At 5 ppm, the sensor's resistance decreases over time, showing a trend that is very similar to the transient response of pure 1-pentanol (Figure 5b top). After increasing the concentration to 50 ppm, it was observed that the sensor's resistance trend over time (Figure 5b bottom) is not sufficiently different from the transient responses to binary mixtures to be usable for the identification of the compounds in the mixture, although the presence of hexanal vapors is recognizable by the steep resistance decrease.

#### **4. Conclusions**

In the work presented, a resistive sensor based on ZnO oxide was prepared and tested for possible use in the monitoring of food degradation phenomena. The ZnO sensor showed a good sensitivity to low concentrations of hexanal, the target compound used in this work as an indicator of meat degradation. In a realistic scenario, the sensor must be able to discriminate among other organic volatiles released at the same time, so tests of the sensitivity were carried out by exposing the sensor to different mixture of vapors of the main competing organic compounds, 1-pentanol and 1-octen-3-ol. In this condition, the sensitivity to hexanal was reduced in the range of low concentrations (5–10 ppm) while at 50 ppm, the sensor's response was comparable with the hexanal quantity. The experiments with binary and ternary mixtures showed, however, that the transient response of the ZnO sensor was significantly influenced by the presence of hexanal in the vapor mixture at all the concentrations tested. Although not so evident in terms of the intensity of the signal R0/R, the detection of hexanal in the vapor mixtures was characterized by a steep decrease with time of the sensor's resistance even at low concentrations, which was not shown by the other organic components.

The ZnO sensor belongs to the family of conductometric sensors and for this reason, it is affected by some common limitations, such as reduced selectivity, electrical drift, and response reproducibility. The results obtained in this study indicate the possible use of ZnO for the monitoring of food degradation; however, further characterization of the material behavior is needed, and durability and repeatability studies, to confirm the observed potential regarding its use as a sensor.

**Author Contributions:** Conceptualization, L.B., A.D. and P.F.; methodology, A.F., A.G. and L.B.; formal analysis, L.B. and A.F.; investigation, A.F. and A.G.; data curation, A.F. and A.G.; writing original draft preparation, A.F. and A.G.; writing—review and editing, L.B. and P.F.; supervision L.B., A.D. and P.F. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by Regione Calabria, POR Calabria FESR/FSE 2014-2020: Asse 12 Azione 10.5.6 "Mobilità internazionale di dottorandi".

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**