CN118291373A - Application of thiazolidinedione PPAR gamma agonist in promoting fat survival after fat transplantation - Google Patents

Abstract

The invention discloses application of thiazolidinedione PPAR gamma agonists in promoting fat survival after fat transplantation, which utilizes PPAR gamma agonist drugs to regulate adipocyte differentiation and maturation, and further improves the survival rate of adipose tissues and the retention rate of fat volume after fat transplantation by promoting regeneration of transplanted adipocytes and increase of adipocyte volume; the lipid regeneration is promoted by regulating the fat cell metabolic pathway, in particular by activating PPARgamma, and can be used for solving the problems of excessive fat necrosis, low fat survival rate and low fat volume retention rate after fat transplantation operation performed for various reasons (including but not limited to congenital or acquired local depression or fat atrophy of the face or other parts of the body surface, or improvement of insufficient body surface capacity of the face or other parts of a normal person for the purpose of cosmetology, or body surface organ regeneration).

Description

Application of thiazolidinedione PPARγ agonists in promoting fat survival after fat transplantation

Technical Field

The present invention relates to the field of biomedicine technology, and in particular to the use of thiazolidinedione PPARγ agonists in promoting fat survival after fat transplantation.

Background technique

Human adipose tissue is mainly composed of white fat (WAT) and brown fat (BAT), of which white fat plays an important role in energy storage, thermal insulation and organ protection. The increase of white adipose tissue is mainly achieved through the proliferation (increase in number) or hypertrophy (increase in volume) of adipocytes. This physiological process is not only related to the energy metabolism balance of an individual, but also directly affects the beauty and health of the body surface.

In the practice of plastic surgery and medical cosmetology, autologous fat has become an indispensable material for improving facial contours, enlarging superficial organs, and reconstructing soft tissues of organs, due to its rich plasticity. One of the mechanisms of facial aging is believed to be the gradual reduction of the subcutaneous fat layer, which causes the skin to sag and wrinkles to form. Therefore, increasing the amount of subcutaneous fat can not only promote the visual effect of facial rejuvenation, but also is an important way to repair or improve the function of superficial organs.

Fat transplantation, also known as autologous fat filling, is widely used in the field of beauty and reconstruction. The procedure involves extracting fat from a certain part of the patient's body, processing it appropriately, and then injecting it into other parts. However, the further development of fat transplantation is currently subject to an important constraint, namely the low survival rate of postoperative fat. The survival rate after fat transplantation is generally between 30% and 70%. The low survival rate leads to postoperative fat necrosis and absorption, which affects the certainty of the efficacy. This problem seriously limits the widespread promotion and implementation of fat transplantation. Many cases require secondary or even multiple transplants to achieve better results, which not only increases medical expenses but also consumes a lot of medical resources. Although the academic community has widely studied how to improve the survival rate after fat transplantation, there is currently no definite and effective method to significantly improve the survival rate of fat, and there is also a lack of treatment options on the market that can improve the local survival rate of fat through drugs.

Summary of the invention

The purpose of the present invention is to provide an application of a thiazolidinedione PPARγ agonist in promoting fat survival after fat transplantation in order to solve the above-mentioned problems. The present invention can not only promote the survival rate of fat after transplantation, but also promote local fat cell regeneration by targeted regulation of the metabolic pathway of fat cells. It is a safe and effective solution to improve the survival rate of fat after fat transplantation.

The present invention achieves the above-mentioned purpose through the following technical solutions:

The first aspect of the present invention provides the use of a thiazolidinedione PPARγ agonist in promoting the differentiation of normal human subcutaneous preadipocytes into mature adipocytes in vitro.

The second aspect of the present invention provides the use of a thiazolidinedione PPARγ agonist in or after an autologous fat transplantation operation to promote fat regeneration in the transplant and improve the postoperative fat survival rate and volume retention rate.

The third aspect of the present invention provides the use of a thiazolidinedione PPARγ agonist administered locally in or around a fat transplant to promote fat regeneration around the transplant site and increase the amount of adipose tissue.

The fourth aspect of the present invention provides the use of thiazolidinedione PPARγ agonists in the preparation of medicines: for promoting fat regeneration after fat transplantation surgery, improving postoperative fat survival rate and volume retention rate; promoting fat regeneration around the transplantation site and increasing the amount of adipose tissue.

The medicine is: 1. A therapeutically effective amount of a thiazolidinedione compound, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier for uniform mixing with a fat graft during a fat transplantation operation; 2. A therapeutically effective amount of a thiazolidinedione compound, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier for local administration after the fat transplantation operation; local administration routes include but are not limited to transdermal administration, microneedle injection, and local injection.

The PPARγ agonist described in the present invention is a thiazolidinedione drug, including but not limited to rosiglitazone and pioglitazone.

The present invention utilizes peroxisome proliferator-activated receptor gamma (PPARγ) agonist drugs, taking rosiglitazone and pioglitazone as examples, to promote fat survival and adipocyte regeneration after fat transplantation. PPARγ is a nuclear receptor that plays a vital role in regulating adipocyte differentiation and lipid metabolism. By activating PPARγ, the maturation and differentiation of pre-adipocytes into adipocytes can be promoted, thereby improving the survival rate of adipose tissue and the retention rate of fat volume after fat transplantation.

PPARγ agonists bind to PPARγ and activate its transcriptional activity, thereby affecting the expression of multiple downstream genes. These genes are involved in multiple processes such as adipocyte differentiation, lipid synthesis, storage, and glucose metabolism. Specifically, the effects of PPARγ agonists have the following effects:

1. Promotion of adipocyte differentiation: PPARγ is a key factor controlling the transformation of preadipocytes into mature adipocytes. Activating PPARγ can promote preadipocytes to express adipogenesis-related genes, such as adiponectin and fatty acid binding protein, thereby promoting the maturation of adipocytes.

2. Increased lipid synthesis and storage: Activation of PPARγ can also increase the expression of lipid synthesis-related enzymes, such as fatty acid synthase (FAS) and glucose transporter 4 (GLUT4), promoting the synthesis and storage of fatty acids and triglycerides.

3. Metabolic normalization: By regulating lipid metabolism, PPARγ agonists not only promote the increase of adipose tissue, but also help improve insulin sensitivity and reduce inflammation levels, thereby normalizing the metabolic state to a certain extent.

The beneficial effects of the present invention are:

1. The present invention develops for the first time a local adipose tissue administration dosage form of a thiazolidinedione PPARγ agonist; unlike traditional oral preparations, the local administration dosage form avoids the process of gastrointestinal digestion and systemic blood circulation, thereby limiting the effect of the drug to the fat cells in the target area; reducing the systemic side effects of the drug, while effectively regulating the function of fat cells in the local area.

2. In the prior art, thiazolidinediones such as rosiglitazone, pioglitazone and troglitazone are mainly used to treat diabetes by increasing the sensitivity of tissues to insulin. The inventors of the present application have discovered that this type of PPARγ agonist has the ability to regulate the differentiation and maturation of adipocytes inside adipose tissue. This mechanism of action promotes the regeneration of adipocytes in the fat transplantation area and the expansion of their volume, thereby significantly improving the survival rate of adipose tissue and the fat volume retention rate. In addition, thiazolidinediones PPARγ agonists can also stimulate fat regeneration around the transplantation area and increase the total amount of adipose tissue. Based on these two mechanisms, the present invention can effectively improve the clinical efficacy after fat transplantation and avoid poor efficacy or multiple transplantation operations caused by low survival rate of transplanted fat.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

FIG. 1a is a diagram showing the oil red staining result of adipocytes supplemented with rosiglitazone in Example 1 of the present invention.

FIG. 1 b is a diagram showing the oil red staining result of adipocytes in which pioglitazone is added in Example 1 of the present invention.

FIG. 2 is a diagram showing the oil red staining result of adipocytes without adding any drug in Example 1 of the present invention.

FIG. 3a is a photograph of mice fat mixed with rosiglitazone transplanted on the back 4 weeks after Example 2 of the present invention.

FIG. 3 b is a photograph of mice fat mixed with pioglitazone transplanted on the back 4 weeks after Example 2 of the present invention.

FIG3 is a photograph of the back of mice with fat unmixed with drugs grafts taken 4 weeks after implantation in Example 2 of the present invention.

FIG. 4 a is a photograph of fat transplanted onto the back of mice in Example 3 of the present invention 4 weeks after regular injection of rosiglitazone.

FIG. 4 b is a photograph of mice fat transplanted on the back 4 weeks after regular injection of pioglitazone in Example 3 of the present invention.

FIG. 4c is a photograph of fat transplanted into the back of mice in Example 3 of the present invention after regular injection of physiological saline for 4 weeks.

FIG. 5 is a microscopic photograph of the original adipose tissue surrounding the mouse fat transplant in Example 4 of the present invention.

FIG. 6 a is a microscopic photograph of the original fat tissue around the graft after rosiglitazone was injected into the graft in Example 4 of the present invention.

FIG. 6 b is a microscopic photograph of the original fat tissue around the graft after pioglitazone was injected into the graft in Example 4 of the present invention.

Detailed ways

To make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be described in detail below. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other implementation methods obtained by ordinary technicians in this field without creative work belong to the scope of protection of the present invention.

Example 1

In vitro induction experiment of human subcutaneous preadipocytes;

Normal human subcutaneous adipose tissue was obtained, and preadipocytes were isolated and cultured. The preadipocytes of the experimental group were cultured in adipogenic induction medium + 100umol/ml rosiglitazone or adipogenic induction medium + 150umol/ml pioglitazone, respectively, and the control group was cultured in adipogenic induction medium. After 48 hours, Oil Red O staining was performed to detect the formation of lipid droplets in adipocytes, as shown in Figures 1a, 1b, and 2. The red part is the stained lipid. Human subcutaneous preadipocytes can be more efficiently induced to differentiate into adipocytes by rosiglitazone and pioglitazone, while the control group cannot be efficiently induced to differentiate into adipocytes.

Example 2

Mouse autologous fat transplantation experiment:

As shown in Figure 3a, Figure 3b, and Figure 3c, after the mice were anesthetized, the inguinal skin was cut open to obtain the inguinal fat pads on both sides, which were cut into pieces and mixed with 100umol/ml rosiglitazone and 150umol/ml pioglitazone, mixed and placed in a syringe, weighed and recorded the original weight, and then transplanted into the subcutaneous space on the back of the mice. After 4 weeks, the samples were observed, weighed, and tested; a blank control was set for each group.

The results showed that the average weight of the back fat grafts of mice with rosiglitazone added was 70.12% of the original weight after 4 weeks, and the average weight of the back fat grafts of mice with pioglitazone added was 72.30% of the original weight after 4 weeks, while the average fat weight of the control group was only 45.24% of the original weight. The difference was statistically significant; it confirmed that PPARγ agonist drugs such as rosiglitazone and pioglitazone can effectively improve the survival rate of fat when mixed with fat grafts.

Example 3

Mouse autologous fat transplantation experiment:

As shown in Figures 4a, 4b, and 4c, after the mice were anesthetized, the inguinal skin was cut open to obtain the inguinal fat pads on both sides, mixed and placed in a syringe, weighed and recorded the original weight, cut into pieces and transplanted into the subcutaneous space on the back of the mice. Thereafter, the fat grafts were injected once a week, and the drug concentrations were as follows: 100umol/ml rosiglitazone, 150umol/ml pioglitazone, and the control group was injected with saline, and the injections were continued for 4 weeks. After 4 weeks, the samples were observed, weighed, and tested.

The results showed that the average weight of the back fat grafts of mice injected with rosiglitazone was 76.91% of the original weight 4 weeks later, and the average weight of the back fat grafts of mice injected with pioglitazone was 73.46% of the original weight 4 weeks later, while the fat weight of the control group was only 51.29% of the original weight. The difference was statistically significant; it confirmed that intrafacial injection of PPARγ agonists such as rosiglitazone and pioglitazone into fat grafts can effectively increase the survival rate of fat.

Example 4

Mouse autologous fat transplantation experiment:

After the mice were anesthetized, the inguinal skin was cut open to obtain the inguinal fat pads on both sides, mixed and placed in a syringe, and then transplanted into the subcutaneous space on the back of the mice. After that, the fat grafts were injected once a week, and the drug concentrations were as follows: 100umol/ml rosiglitazone, 150umol/ml pioglitazone, and the control group was injected with normal saline for 4 consecutive weeks. After 4 weeks, the in situ subcutaneous tissue within 2mm around the grafts was taken for HE staining;

As shown in Figures 5, 6a and 6b, after the fat graft was injected with rosiglitazone and pioglitazone, it was observed that the volume of the fat cells in the subcutaneous tissue around the transplanted area expanded and the number increased, which indicates that the local application of rosiglitazone and pioglitazone in the fat graft can effectively promote the volume growth of the fat cells and the synthesis of lipids in the original fat tissue around the graft.

Example 5

The following description exemplifies the use of a thiazolidinedione PPARγ agonist drug mixed with a fat graft to improve the survival rate of the fat graft

A male patient with congenital hemifacial atrophy wanted to improve his facial asymmetry and sought surgical improvement. The doctor performed autologous fat transplantation on him. After extracting fat from the thigh, about 50ml of pure fat was obtained through centrifugal purification. An appropriate amount of rosiglitazone solution was added to it to make the final concentration reach 100umol/ml. After fully mixing, it was injected and transplanted subcutaneously in the area of facial atrophy. After 3 months, clinical observation showed that the fat survival rate was good, the face was basically restored to symmetry, the patient was satisfied with the surgical results, and no secondary transplantation was required.

Example 6

The following description exemplifies the use of thiazolidinedione PPARγ agonist drugs injected locally into fat grafts to improve the survival rate of fat grafts

A female patient wanted to undergo breast augmentation surgery, and the doctor performed autologous fat augmentation for her. After extracting fat from the thigh, 400ml of pure fat was obtained after centrifugation, and then injected and transplanted into the retromammary space layer in the breast. On the second day after the operation, the doctor began to perform local injections of rosiglitazone solution for her. The injection layer was the retromammary space, and the injection concentration was 100umol/ml. The injection was performed once a week for a total of 3 times. After 3 months, clinical observation showed that the fat survival rate was good, the volume of both breasts was maintained well, and there was no obvious shrinkage in volume. The patient was satisfied with the results of the operation and no secondary transplantation was required.

Example 7

The following description exemplifies the use of local microneedle transdermal injection of thiazolidinedione PPARγ agonist drugs into fat grafts to improve the survival rate of fat grafts

A female patient felt that her cheeks were sunken, which affected her appearance, and she wanted to undergo cheek augmentation surgery. The doctor performed autologous fat transplantation on her. After extracting abdominal fat, about 10 ml of pure fat was obtained through centrifugal purification, and then injected and transplanted into the subcutaneous layer of the sunken cheeks on both sides. On the second day after the operation, the doctor performed microneedle transdermal injection treatment of rosiglitazone solution (also known as mesotherapy or mesodermal injection, commonly known as water light needle injection) on the transplanted part. The injection instrument was the Dermashine water light injection instrument. The injection level was the intradermal and subcutaneous superficial layer of the cheek. The injection concentration was 100umol/ml, and the injection was once a month for a total of 3 injections. After 3 months, clinical observation showed that the fat survival rate was good, and the cheeks on both sides were flat without obvious depression. The patient was satisfied with the results of the operation and did not need a second transplant.

Example 8

The following description exemplifies the use of a thiazolidinedione PPARγ agonist drug for local administration into a fat graft to promote fat regeneration around the graft site

A female patient found that her bilateral temporal areas gradually became sunken and fat was lost as she aged, which affected her appearance. She hoped to undergo temporal augmentation surgery. The doctor performed autologous fat transplantation on her. After extracting abdominal fat, about 20 ml of pure fat was obtained by centrifugal purification, which was then injected and transplanted into the temporal middle fascia layer of the temporal part. On the second day after the operation, the doctor began to perform local injections of rosiglitazone solution. The injection layer was the temporal middle fascia layer of the temporal part. The injection concentration was 100umol/ml, once a week, for a total of 3 injections. After 3 months, clinical observation showed that the fat survival rate was good, and the bilateral temporal areas were flat without obvious depression. The patient was satisfied with the surgical results and did not need a second transplant. The patient underwent facial ultrasound examination, which showed that the transplanted fat in the temporal middle fascia layer survived well, and the thickness of the temporal subcutaneous fat layer increased compared with other areas of the face. It was confirmed that the improvement of the depression of the temporal part was the result of the combined effect of the transplanted fat survival in the temporal middle fascia layer and the thickening of the subcutaneous fat.

The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can easily think of changes or replacements within the technical scope disclosed by the present invention, which should be covered within the protection scope of the present invention. In particular, in view of the principle that PPARγ agonists promote fat regeneration, the present invention is not limited to the two PPARγ agonist drugs, rosiglitazone and pioglitazone, but also includes a series of compounds with the same or similar PPARγ activation ability. This means that any PPARγ agonist that can promote fat survival after fat transplantation through the above mechanism can be within the protection scope of this patent. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims. It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further explain various possible combinations. In addition, the various different embodiments of the present invention can also be combined arbitrarily, as long as they do not violate the idea of the present invention, they should also be regarded as the content disclosed by the present invention.

Claims (6)

1. Use of a thiazolidinedione ppary agonist to promote in vitro differentiation of normal human subcutaneous precursor adipocytes into mature adipocytes.

2. The application of thiazolidinedione PPARgamma agonist in autologous fat transplantation operation or after operation for promoting fat regeneration in implant and improving postoperative fat survival rate and volume retention rate.

3. Use of a thiazolidinedione pparγ agonist in or around a fat graft for topical administration to promote regeneration of fat around the site of the graft.

4. Use of a thiazolidinedione pparγ agonist in the preparation of a medicament: is used for promoting fat regeneration after fat transplantation operation and improving the survival rate and volume retention rate of the fat after operation; promote regeneration of fat around the transplanted site and increase the amount of adipose tissue.

5. The use according to claim 4, wherein the pharmaceutical product is: in fat transplantation surgery, a therapeutically effective amount of a thiazolidinedione compound, or a pharmaceutically acceptable salt or prodrug thereof, for intimate admixture with a fat graft, and a pharmaceutically acceptable carrier; a therapeutically effective amount of a thiazolidinedione compound, or a pharmaceutically acceptable salt or prodrug thereof, for topical administration within or around a graft after a fat transplantation procedure, and a pharmaceutically acceptable carrier; the topical route of administration includes transdermal administration, microneedle injection, and topical injection.

6. The use according to any one of claims 1 to 5, wherein the thiazolidinedione pparγ agonist comprises rosiglitazone, pioglitazone.