**3. Treatment of pain based on anti-inflammation and regeneration**

Musculoskeletal disorders are the most frequent cause of disability in the modern world, and the prevalence of these diseases is rising at an alarming rate. The most prominent reason for loss of joint mobility and function is chronic pain, which leads to impaired quality of life. Current therapies to alleviate pain have limited effectiveness, and some drugs produce unwanted negative side effects, thereby precluding their long-term use.

Nociceptive receptors are located throughout the joint. It has been identified in the capsule, ligaments, menisci, periosteum, and subchondral bone. If a noxious mechanical factor or inflammatory mediator is applied to the joint, the firing rate of the afferent nerve increases dramatically, and the central nervous system interprets this nociceptive activity as pain [23]. Transient pain is induced and serves as a physiological warning at brief, high-intensity stimuli, which produce little or no tissue damage. However, in chronic pain conditions, there may be spontaneous pain, as well as intermittent pain, which is induced by persistent inflammation from structural damage or functional degeneration. Chronic pain is also associated with complex changes in peripheral and central signal processing [24].

It is accepted that inflammation and the inflammatory response play pivotal roles in the occurrence, as well as progress of pain. The biochemical mediators of inflammation include cytokines, neuropeptides, growth factors, and neurotransmitters. Irrespective of the type of pain whether it is acute or chronic pain, peripheral or central pain, nociceptive or neuropathic pain, the underlying origin is inflammation and inflammatory response. Activation of pain receptors, transmission of pain signals, and modulation of neuroplasticity all belong to a continual spectrum of inflammation and inflammatory response.

Every pain syndrome has an inflammatory profile consisting of the inflammatory mediators that are present in the pain syndrome. The inflammatory profile may have variations from one person to another and may have variations in the same person at different times. Various symptoms of pain syndromes are attributed from corresponding inflammatory profiles of discrete pain syndromes. The key to treat pain syndromes is inhibiting the production of inflammatory mediators at the same time regenerating injured or degenerative tissues. The term "regeneration" is used to describe the phenomena that allow an organism to reconstitute the structure damaged by injury and recover the functional homeostasis. A successful outcome is one that results in less inflammation, more regeneration, and thus less pain.

due to anti-inflammatory effects from each member. Numerous uncontrolled trials, as well as a limited number of controlled trials, have been published after short-term or long-term use of acupuncture in the treatment of inflammatory diseases. The direct and indirect effects of acupuncture on regulation of inflammatory mediators such as neuropeptides, cytokines, and vasoactive substances have been assessed [36]. Even though there are some pitfalls such as relatively small number of patients and incompletely described methodological procedures, the results clearly show a beneficial effect of acupuncture in the reduction of symptomatic inflammatory response. As well, anti-inflammatory effects of placental extracts were fully evaluated. Porcine placental extract was shown to protect the contact hypersensitivity of skin by modulation of immunoglobulin E production [37]. Animal model studies showed that placental extracts reduced the concentration of free radicals, inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor (TNF), and interleukin-1 (IL-1) at the same time increasing the colony formation of progenitor cells in vitro [38]. Clinical trials of API with placental extracts showed anti-inflammatory effects in pain diseases. Injection of placental extract to acupuncture points ameliorated various inflammation-associated symptoms of complex regional pain syndrome [39, 40]. In osteoarthritic patients, API with placental extract

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improved daily working hours, reduced knee joint swelling, and abated pain [20].

to promote regeneration at the time of regenerative procedure [41].

fibrogenesis, neoangiogenesis, and epithelialization [8].

**extracts**

**5. Regenerative effects of acupuncture point injection with placental** 

Regenerative medicine has the potential to heal or replace tissues and organs damaged by age, disease, or trauma. The current therapy of transplantation of intact organs and tissues to treat organ and tissue failures suffers from limited donor supply and often severe immune complications. These obstacles may potentially be bypassed through the use of regenerative medicine strategies. The field of regenerative medicine encompasses numerous strategies, including use of materials and de novo generated cells, as well as various combinations. Regenerative medicine effectively replaces missing tissues both structurally and functionally, thus contributes to tissue healing. The body's innate healing response may also be leveraged

Placental extracts are obtained by lysing human placental tissues collected from full-term delivery. The extracts do not contain cells but are rich in a wide range of proteins, minerals, amino acids, and steroid hormones. Placenta synthesizes a number of hormones, such as estradiol, progesterone, and chorionic gonadotrophin, which regulate growth and development of the fetus during pregnancy so that placental extracts have the impact on proliferation. Data indicate that placental extracts stimulate proliferation and regenerative processes in various systems. The significant increase in tensile strength and tissue DNA in the animals given human placental extract indicates the extract-induced marked collagen synthesis [42]. Human dermal fibroblasts showed an increased proliferation after treatment of human placental extract [43]. Placental extracts were also shown to enhance the proliferation of cord blood cells in vitro [44]. Animal model studies proved that the placental extract promotes
